Reliability of Alkaline Phosphatase for Differentiating Flare Phenomenon from Disease Progression with Bone Scintigraphy

The flare phenomenon (FP) on bone scintigraphy after the initiation of systemic treatment seriously complicates evaluations of therapeutic response in patients with bone metastases. The aim of this study was to evaluate whether serum alkaline phosphatase (ALP) can differentiate FP from disease progression on bone scintigraphy in these patients. Breast or prostate cancer patients with bone metastases who newly underwent systemic therapy were reviewed. Pretreatment baseline and follow-up data, including age, pathologic factors, type of systemic therapy, radiologic and bone scintigraphy findings, and ALP levels, were obtained. Univariate and multivariate analyses of these factors were performed to predict FP. An increased extent and/or new lesions were found in 160 patients on follow-up bone scintigraphy after therapy. Among the 160 patients, 80 (50%) had an improvement on subsequent bone scintigraphy (BS), while subsequent scintigraphy also showed an increased uptake in 80 (50%, progression). Multiple regression analysis revealed that stable or decreased ALP was an independent predictor for FP (p < 0.0001). ALP was an independent predictor for FP on subgroup analysis for breast and prostate cancer (p = 0.001 and p = 0.0223, respectively). Results of the study suggest that ALP is a useful serologic marker to differentiate FP from disease progression on bone scintigraphy in patients with bone metastasis. Clinical interpretation for scintigraphic aggravation can be further improved by the ALP data and it may prevent fruitless changes of therapeutic modality by misdiagnosis of disease progression in cases of FP.

Cardiac Amyloidosis: A Review of Current Imaging Techniques

Systemic amyloidosis is a rare, heterogenous group of diseases characterized by extracellular infiltration and deposition of amyloid fibrils. Cardiac amyloidosis (CA) occurs when these fibrils deposit within the myocardium. Untreated, this inevitably leads to progressive heart failure and fatality. Historically, treatment has remained supportive, however, there are now targeted disease-modifying therapeutics available to patients with CA. Advances in echocardiography, cardiac magnetic resonance (CMR) and repurposed bone scintigraphy have led to a surge in diagnoses of CA and diagnosis at an earlier stage of the disease natural history. CMR has inherent advantages in tissue characterization which has allowed us to better understand the pathological disease process behind CA. Combined with specialist assessment and repurposed bone scintigraphy, diagnosis of CA can be made without the need for invasive histology in a significant proportion of patients. With existing targeted therapeutics, and novel agents being developed, understanding these imaging modalities is crucial to achieving early diagnosis for patients with CA. This will allow for early treatment intervention, accurate monitoring of disease course over time, and thereby improve the length and quality of life of patients with a disease that historically had an extremely poor prognosis. In this review, we discuss key radiological features of CA, focusing on the two most common types; immunoglobulin light chain (AL) and transthyretin (ATTR) CA. We highlight recent advances in imaging techniques particularly in respect of their clinical application and utility in diagnosis of CA as well as for tracking disease change over time.

199 Lower aortic valve calcium scores by computed tomography scan. A potential new red flag of concomitant cardiac amyloidosis in patients with severe aortic stenosis

Aims Cardiac amyloidosis (CA) and degenerative aortic stenosis (AS) are two diseases often combined but the diagnosis of both these conditions is challenging because these two illnesses share common echocardiographic characteristics. Different predictors have been proposed in the last few years, including clinical, ECG-graphic, and echocardiographic features. To identify a new marker of concomitant CA in patients with severe AS using computed tomography scan (CT). Methods and results Fifty-five patients with severe AS and suspicion of concomitant CA were retrospectively enrolled. Patients with a bicuspid aortic valve, previous aortic valve replacement, or an incomplete diagnostic workup for CA were excluded. Thirty-three patients underwent CT-scan and were included in the final analysis. None of the patients had at laboratory tests suspicion for AL amyloidosis; 12 patients (AS-CA) had positive 99 m Tc-DPD bone scintigraphy (two with visual score 1, eight score 2 and two score 3), 21 patients (AS-alone) had negative bone scintigraphy (visual score 0). AS-CA patients had a median age of 85.5 years (vs. 82) with only one female patient (vs. 8 in the AS-alone group). AVA indexed were almost comparable between AS-CA and AS-alone groups (0.4 vs. 0.3 mm2/m2, P = 0.25). Stroke volume evaluated by pulsed Doppler, maximum and mean gradient were significatively lower in AS-CA group (respectively 30 vs. 41 ml/m2, P = 0.017, 62 vs. 74 mmHg, 0.038 and 33 vs. 46 mmHg, P = 0.022) with a higher percentage of paradoxical low flow-low gradient aortic stenosis in AS-CA group (7 patients, 58% vs. 3 patients in AS-alone 14%, P = 0.027), in line with the literature. ECG at first presentation in AS-CA group showed atrial fibrillation in eight patients (67%), vs. two patients in the AS-alone group (10%), and lower QRS voltages (peripheral QRS score 40 mV vs. 51 mV, P-value = 0.017; total QRS score 113 mV vs. 155 mV, P-value = 0.005). The echocardiogram showed a more thickened IVS and PW in AS-CA patients (17 vs. 15 mm, P = 0.05 and 15 vs. 14 mm, P = 0.013), an increased left ventricular mass (441 vs. 356 g, P = 0.036) with a reduction of longitudinal systolic function (septal S wave at TDI 4.4 vs. 5.2 cm/s, P = 0.026, lateral S wave 4.1 vs. 5.6 cm/s, P = 0.024) and a lower myocardial contraction fraction (12% vs. 14%, P = 0.036). CT-aortic valve calcium was valued and quantified by an experienced operator. A statistically significant difference between AS-CA and AS-alone groups was observed in calcium score (3345 vs. 4785 Hounsfield units, P = 0.037) calcium volume (2411 vs. 3626 mm2, P = 0.03) and calcium mass (687 vs. 1147 g, P = 0.023). Conclusions This study is the first to our knowledge to use relative aortic valve calcium score evaluation from CT imaging to define patients with severe AS with or without concomitant CA in addition to the classical clinical, ECG graphic, and echocardiographic features. CT-aortic valve calcium burner was significatively lower in patients with concomitant CA.

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.

Two-Year Evaluation of the German Clinical Amyloidosis Registry

Introduction Currently there are no sufficient epidemiology data on systemic amyloidosis in Germany. Our aim was to collect epidemiological data on amyloidosis diseases to determine incidence and distribution of amyloidosis types in Germany. In addition, data on diagnosic pathways, demographic, clinical and biological factors, quality of life (Qol) and overall survival (OS) have been collected. Methods: The actual registry population consists of the first n=1000 reported cases of newly diagnosed amyloidosis patients between 4.1.18 - 21.11.19. Data cutoff of the analysis was June 30, 2021. Patients were included in the registry by two main ways: personal presentation at the amyloidosis outpatient clinic or phone contact of the attending physician to the Amyloidosis Center. Inclusion criteria were either a Congo Red positive tissue sample or unequivocal findings in bone scintigraphy (ATTR amyloidosis). Patients were contacted every 6 months to obtain QoL data using EORTC QLQ-C30, EQ-5D-5L and SF36-v2 questionnaires. This registry was financially supported by Prothena. Results: During this time period 963 of the first 1000 reported newly diagnosed patients (37 pts. did not fulfil inclusion criteria and were excluded) were evaluated mainly through the amyloidosis outpatient clinic (n=581, 60.3%). Seventy-three percent of cases were male (n=706). The median age at diagnosis was 71 years and differed between the AL pts.(65,5 years) and ATTRwt (78 years) patients. The subgroup distribution was as follows: 438 (45,5%) AL pts., 318 (33%) ATTRwt pts., 35 (3,6%) ATTRv pts, 60 (6,2%) ATTR of unknwon subtype, 66 (6,8%) local amyloidosis, 30 (3,1%) AA amyloidosis, 12 (1,2%) others and 4 (0,4%) not typed. Diagnosis was confirmed by biopsy in 88% and in 12% by bone scintigraphy. The most commonly involved organs were heart (n=733, 76,1%) and kidney (n=305, 31,7%). Cardiac staging systems were used for systemic AL (Kumar et al., 2014) with heart involvement and ATTR amyloidosis (Gillmore et al., 2018). Data on survival were available in all cases (median follow-up 27 months). During the observation time 249 patients died (60 ATTRwt and 153 AL pts., 36 other, figure). The most frequent cause of death was amyloidosis itself (n=191, 76,7%). Seven (2,8%) patients died due to therapeutic complications. Compared to ATTRwt patients with cardiac AL amyloidosis had a higher hazard to die, 1 year survival was 78.96% (95% CI 75.23% - 82.88%) compared to 94.30% (95% CI 91.80% - 96.90%), respectively. In multivariate analysis (including age, cardiac staging systems and time from symptoms to diagnosis) factors associated with worse OS were increasing age for AL pts. (HR 1.04, p&lt;0,001 for AL, and highest cardiac stage (HR 2.33, p=0,001 for AL and 5.69, p&lt;0,001 for ATTRwt). Conclusion: The first 2 years of the German clinical amyloidosis registry have been successful to generate valuable clinial data for all types of amyloidosis from newly diagnosed patients. Subtyping the amyloid precursor protein was successful in nearly all patients. The most common form is AL followed by ATTRwt amyloidosis. Heart involvment was very common and pts. were mostly in advanced cardiac stage. Main cause of death was amyloidosis related. In 2020 we have started an extended registry (financially supported by Janssen) including anonymized biopsy reports from reference pathologists. With this approach we will probably obtain more precise data on incidence in Germany. Figure 1 Figure 1. Disclosures Hegenbart: Alnylam: Honoraria; Akcea: Honoraria; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Research Funding; Prothena: Research Funding. Carpinteiro: Janssen: Honoraria; BMS: Honoraria; GSK: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Müller-Tidow: Pfizer: Research Funding; Bioline: Research Funding; Janssen: Consultancy, Research Funding. Schönland: Janssen: Honoraria, Other: Travel grants, Research Funding; Prothena: Honoraria, Other: Travel grants; Pfizer: Honoraria; Takeda: Honoraria, Other: Travel grants; Sanofi: Research Funding.

P085 Chronic recurrent multifocal osteomyelitis: about 2 cases

Background Chronic recurrent multifocal osteomyelitis (CRMO) also known as aseptic osteomyelitis is a rare auto-inflammatory disease with an incidence estimated at 4/100 000 population [1]. The aim of our work was to report two cases of CRMO that illustrate challenges in the diagnosis of this rare disease. Method We report the case of two patients diagnosed with CRMO. Clinical, biological and radiological data as well as disease outcomes were described. We also collected data about treatment modalities. Results Two patients aged of 7 and 10 years respectively, without any notable pathological history, presented recurrent episodes multifocal painful swelling of limbs. In the first case, the symptoms concerned the left ankle and knee as well as the left hip, all associated with lameness and an altered general condition, with neither fever nor skin manifestations. In the second case, the swelling involved the right shoulder, right hip and the left ankle. There was no elevated CRP or ESR in any of patients. Immunological status (RF, anti-CCP, AAN) as well as the HLA-B27 antigen test were negative. In the first patient, standard radiographs showed lytic lesions of the proximal metaphysis of the tibia, the greater trochanter and the left lateral malleolus. MRI of the pelvis, knee, and sternum of the first patient revealed edematous involvement of the left greater trochanter, the right ilium, the proximal metaphyseal region of the tibia and the right edge of the sternum, whereas in the second patient, a whole-body MRI showed inflammatory signs over the left greater trochanter, the insertion of the gluteus medius and obturator externus, right trochanteric bursitis and oedema of the entire right ilium. In the first patient, bone scintigraphy showed intense uptake of radioisotopes in the left ilium, the 7 th right costo-vertebral junction, the trochanteric mass, the upper end of the tibia and the lower end of the left fibula. Bone biopsy showed bone remodeling in both cases without evidence of infection or tumor. The diagnosis of CRMO was retained, supported by the prompt response to NSAIDs and short-term corticosteroid therapy. However, the second patient presented, 8 years later, pain in the sterno-clavicular joint as well as the right hip. A relapse of the disease was confirmed by MRI. Therapeutic escalation with zoledronic acid 0.025 mg/kg intravenous infusion every six months allowed the resolution of the symptoms. Conclusion These observations illustrated a rare disorder in children, characterized by lytic lesions predominantly in the metaphysis of long bones. Bone scintigraphy allowed an early assessment of disease extension and histological examination ruled out a malignant tumor and an infection. The first-line treatment is anti-inflammatory drugs. In case of failure, bisphosphonates seem to be effective.

Phenotypic presentation trends of transthyretin amyloid cardiomyopathy: are we getting better?

Introduction Transthyretin amyloid cardiomyopathy (ATTR-CM) is being increasingly recognized due to recent advances in non-invasive imaging notably bone scintigraphy and newer effective therapies - particularly tafamidis, which was shown to improve survival and decrease heart failure hospitalizations in the ATTR-ACT trial. Earlier tafamidis use appeared to be more beneficial, as reflected by NYHA class I and II patients being associated with lower mortality and hospitalizations compared to NYHA class III. Increased awareness will likely lead to an increasing number of ATTR-CM patients being diagnosed with concerns regarding applicability of ATTR-ACT criteria on these patients. Purpose To investigate ATTR-CM phenotypic presentation trends based on initial clinical, biomarkers and transthoracic echocardiographic (TTE) data. Methods From 2005–2020, 116 ATTR-CM patients were seen at our amyloidosis center, who were stratified into 3 time periods based on the date of diagnosis: Early (21 patients, pre-2016), Mid (46 patients, 2016–2018), and Recent (49 patients, 2018–2020). ATTR-CM diagnosis was established based on the standard criteria of confirmed ATTR variant + typical TTE features; histological confirmation endomyocardial biopsy; or typical diffuse cardiac tracer uptake on bone scintigraphy while ruling out light chain amyloidosis. With less typical imaging, cardiac MRI typically served as a confirmatory test prior to pursuing histological confirmation. Demographics, cardiac biomarkers, diagnostic method used, and TTE variables that raise the suspicion of ATTR-CM were compared across time periods using one-way ANOVA test and Fischer's exact test. Results There was a significant change in the predominant method of diagnosis with the majority of patients in the Early time period diagnosed by endomyocardial biopsy, whereas in the Recent time period the majority of patients were diagnosed via pyrophosphate scintigraphy (Figure). Despite increasing number of patients being diagnosed, the clinical phenotype at diagnosis did not change significantly with similar proportion of patients NYHA class I/II, median daily diuretic dose, biomarkers, having at least one heart failure hospitalization prior to diagnosis, and similar TTE phenotype (Table). Only the age at diagnosis significantly increased across time periods. Women represented the minority of patients across all time periods. Conclusion Despite the increased awareness of ATTR-CM, there have been no major changes in the clinical, cardiac biomarker, or TTE phenotype on presentation in patients referred to our center for suspicion or a diagnosis of ATTR-CM. Our findings challenge the assumption that patients with ATTR-CM are being identified earlier with milder phenotypes. Women with ATTR-CM likely remain largely undiagnosed in our community. Continued education and knowledge dissemination are essential to identify ATTR-CM patients earlier to achieve better outcomes in this population. FUNDunding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Pranav Chandrashekar is supported by an educational grant from Pfizer, Inc paid to Oregon Health and Science University. Table 1