Real-Life Evaluation of an Algorithm for the Diagnosis of Cardiac Amyloidosis.

OBJECTIVE: To evaluate the real-life use of a modified Gillmore algorithm with a "one-stop-shop" approach, bone scintigraphy (BS), a monoclonal gammopathy test (GT), a salivary gland biopsy (SGB), and genetic testing performed at the same time for the diagnosis of cardiac amyloidosis at the French National Reference Centre for Cardiac Amyloidosis (Henri Mondor Hospital, Créteil, France). METHODS: This retrospective cohort study included a total of 1222 patients with suspected amyloidosis who underwent BS and GT between June 2008 and May 2019. RESULTS: Of 1222 patients, 349 had no cardiac uptake on BS and negative GT (BS-/GT-), 276 were BS-/GT positive (GT+), 420 patients were BS+/GT-, and 177 were BS+/GT+. Our one-stop-shop check-up enabled us to diagnose 892 (72.9%) patients; 330 (27.0%) patients required additional examinations, such as mass spectrometry and/or a cardiac biopsy. This subset notably included 112 patients with amyloid light chain amyloidosis. More than 64% of the patients with transthyretin amyloidosis or another type of amyloidosis were diagnosed during the one-stop shop visit. Sensitivity and specificity of BS for transthyretin amyloidosis diagnosis was 99% and 96%, respectively. For amyloid light chain diagnosis, sensitivity and specificity were 100% and 76%, respectively, for GT and 54% and 100%, respectively, for SGB. Of 910 transthyretin genetic tests, 205 (17%) detected mutations. CONCLUSION: The results of our real-life cohort study confirmed the ability of a one-stop-shop approach with a modified Gillmore algorithm to diagnose cardiac amyloidosis and the interest of simultaneous testing for earlier diagnosis. The SGB has diagnostic value because it is easy, quick, and less invasive than a cardiac biopsy.

History of extracardiac/cardiac events in cardiac amyloidosis: prevalence and time from initial onset to diagnosis.

AIMS: Cardiac amyloidosis (CA) has a poor prognosis which is aggravated by diagnostic delay. Amyloidosis extracardiac and cardiac events (AECE and ACE) may help improve CA diagnosis and typing. The aim of this study was to compare AECE and ACE between different CA types and assess their relationship with survival. METHODS AND RESULTS: This retrospective cohort study conducted in France from June 2008 to May 2019, at the Henry Mondor Hospital. This cohort included 983 patients with CA. Mean age at inclusion was 73.1 ± 11.4 years, 726 (75.1%) were male and the mean body mass index was 24.5 ± 4.1 kg/m2 . Among them, 321 had immunoglobulin light chain (AL) amyloidosis, 434 had wild-type transthyretin (ATTRwt), and 212 had hereditary transthyretin (ATTRv). The first AECE and/or ACE occurred at a mean age of 63 ± 11 years for AL and ATTRv, and 70 ± 12 years for ATTRwt (P < 0.01). The median (Q1-Q3) delay between declaration of the first events and diagnosis varied from 11.1 (5.9; 34.8) months for AL to 92.2 (39.0; 174.7) months for ATTRwt (P < 0.01). The nature of the onset of AECE or ACE varied based on amyloidosis type, heart failure symptoms for AL (26%) and integumentary symptoms for ATTRv with cardiologic or mixed phenotype (39%) and ATTRwt (42%). In AL and ATTRwt, a short delay between the onset of the first AECE or ACE and diagnosis was associated with reduced survival rate (log-rank test P-value <0.01). CONCLUSIONS: This study highlights the impact of amyloidosis type and evolution on diagnostic delay and on prognosis. Physicians must be aware and vigilant in front of extracardiac and cardiac events to considerably improve early diagnosis of amyloidosis.

18F-sodium fluoride PET/MRI myocardial imaging in patients with suspected cardiac amyloidosis.

BACKGROUND: We evaluated the diagnostic performance of 18F-NaF PET/MRI in patients with suspected cardiac amyloidosis (CA). METHODS: Twenty-seven consecutive patients underwent myocardial PET 1 hour after injection of 4 MBq/kg 18F-NaF with simultaneous MRI including cine-MRI, T1 and T2 mapping, first-pass and late gadolinium enhancement (LGE). 18F-NaF uptake was measured visually and semi-quantitatively by calculating myocardium-to-blood pool (M/B) ratios. CA was confirmed histologically. RESULTS: Transthyretin (TTR)-CA was diagnosed in 16 patients, light-chain (AL)-CA in 7, and no-CA in 4. Visual interpretation of 18F-NaF images revealed a relative increase in myocardial uptake in only 3 patients, all with TTR CA, and a relative decrease in 13, including 7 AL CA, 3 no-CA, and 3 TTR CA. M/B ratios were significantly higher in TTR CA (1.00 ± 0.12) than in AL CA (0.81 ± 0.06, P = 0.001) or in no-CA (0.73 ± 0.16, P = 0.006). The optimal M/B cut-off to distinguish TTR CA from AL CA was ≥ 0.90 (Fischer, P = 0.0005). By comparison, classification of patients using 99mTc-HMDP heart-to-mediastinum ratios with the previously published cut-off ≥ 1.21 reached higher significance (P < 0.0001). Among MRI parameters, myocardial T1, LGE score, and extracellular volume were higher in CA than in no-CA patients, 1409 ± 76 vs 1278 ± 35 ms (P = 0.004), 10.35 ± 5.30 vs 3.50 ± 3.42 (P = 0.03), and 46 ± 10 vs 33 ± 8 % (P = 0.01), respectively. CONCLUSION: 18F-NaF PET/MRI shows good diagnostic performance when semi-quantification is used. However, contrast is low and visual interpretation may be challenging in routine. PET/MRI could constitute a one-stop-shop evaluation of amyloid load and cardiac function in patients needing rapid work-up.

Natural history and impact of treatment with tafamidis on major cardiovascular outcome-free survival time in a cohort of patients with transthyretin amyloidosis.

AIMS: Hereditary (ATTRv) and wild-type (ATTRwt) transthyretin amyloidosis are severe and fatal systemic diseases, characterised by amyloid fibrillar accumulation principally in the heart or peripheral nerves (or both). Since 2012, tafamidis has been used in France to treat patients with ATTRv with neuropathy (alone or combined with cardiomyopathy). Recently, the Phase III ATTR-ACT trial showed that tafamidis decreased the relative risk of mortality in ATTR amyloidosis with cardiomyopathy. The aims of this study were to assess the clinical characteristics of ATTR amyloidosis in a real-life population in comparison to the population included in the ATTR-ACT trial and to assess the impact of tafamidis treatment on major cardiovascular outcome (MCO)-free survival time without cardiac decompensation, heart transplant, or death. METHODS AND RESULTS: From June 2008 to November 2018, 648 patients with ATTR amyloidosis (423 ATTRwt and 225 ATTRv) consecutively referred to the French Referral Center for cardiac amyloidosis were included. A total of 467 (72%) patients matched the inclusion criteria of the ATTR-ACT trial. For the 631 patients with cardiomyopathy, tafamidis treatment was associated with a longer median MCO-free survival time (n = 98): 1565 (1010-2400) days vs. 771 (686-895) days without treatment (log-rank P < 0.001). This association was confirmed after considering confounding factors (age at inclusion, N-terminal pro-B-type natriuretic peptide and amyloidosis type) with a propensity score (hazard ratio 0.546; P = 0.0132). CONCLUSION: In a large cohort of ATTRwt and ATTRv patients, representative of the inclusion criteria of the ATTR-ACT trial, the present results show an association between tafamidis treatment and a lower occurrence of cardiovascular outcomes in a real-life population.

Complete response in anaplastic lymphoma kinase-rearranged oncocytic thyroid cancer: A case report and review of literature.

BACKGROUND: Oncocytic carcinoma of the thyroid is a rare disease, characterized by a poor prognosis and low response rate to radioiodine therapy. Crizotinib is a specific anaplastic lymphoma kinase (ALK) inhibitor, which was initially developed in non-small cell lung cancer. Other solid tumors harboring a translocation in ALK have been described, such as renal carcinoma, thyroid, colorectal, ovarian cancers, and spitzoid melanoma. The research of ALK rearrangements in thyroid tumor is a promising therapeutic track, and treatments need to be explored. CASE SUMMARY: We report the case of a 76-year-old woman with a history of multinodular goiter, who was hospitalized for impairment of her general condition. She was diagnosed with metastatic oncocytic thyroid cancer. Synchrone metastases were found: Multiple mediastinal lymphadenopathies, lytic bone lesions and bilateral mammary lumps. Fluorescence in situ hybridization analysis revealed an ALK rearrangement in 61% of cells. No other mutation was found. A tumor board discussion based on molecular characteristics of the tumor suggested initiating a daily treatment by crizotinib, a specific ALK inhibitor. A positron emission tomography scan performed 4 mo after the initiation of crizotinib showed a complete metabolic response. CONCLUSION: This case highlights an unexpected efficacy of crizotinib in an ALK-rearranged thyroid tumor, and the need of further assessments.

Extracardiac soft tissue uptake, evidenced on early 99mTc-HMDP SPECT/CT, helps typing cardiac amyloidosis and demonstrates high prognostic value.

PURPOSE: Increased cardiac uptake (CU) on early-phase 99mTc-HMDP scintigraphy has demonstrated diagnostic and prognostic values in amyloid transthyretin (ATTR) cardiac amyloidosis (CA). Extracardiac uptake (ECU) has been poorly studied. We assessed the clinical value of ECU, in combination with CU, on 99mTc-HMDP scintigraphy using a novel Methodological Amyloidosis Diagnostic Index (MADI). METHODS: We reviewed all patients referred for suspicion of CA, who underwent 99mTc-HMDP scintigraphy over an 8-year period. ECU, CU, and MADI were determined: MADI0 = neither ECU or CU, MADI1 = ECU alone, MADI2 = CU alone, and MADI3 = ECU + CU. RESULTS: Of 308 eligible patients, 247 had CA, including 75 ATTRv, 107 ATTRwt, and 65 light-chain (AL), while 61 had another cardiopathy (controls). ECU was observed in 29% of CA and 3% of controls. Most frequent sites of ECU were pleuropulmonary (16% of CA, 3% of controls) followed by the digestive tract and subcutaneous tissues. The liver and spleen ECU was only observed in AL-CA (n = 8). CU was only observed in CA patients (n = 187), of whom 182 had ATTR-CA vs. 5 AL-CA, P < 0.001. MADI0 was only observed in controls (97%) and in AL-CA (60%). MADI1 was mainly observed in AL-CA (positive predictive value, PPV = 91%) while MADI2/3 were more frequent in ATTR-CA (PPV = 97%), P < 0.0001. MADI > 0 vs. MADI0 in AL and MADI3 vs. MADI2 in ATTR were associated with a worse prognosis (P = 0.03 and P = 0.002, respectively). CONCLUSIONS: ECU combined with CU demonstrates high diagnostic and prognostic values in CA patients. MADI seems an easy and reliable score in clinical practice.

Renal Infarction and Its Consequences for Renal Function in Patients With Cardiac Amyloidosis.

OBJECTIVE: To describe the prevalence of and risk factors for renal infarction (RI) in patients with cardiac amyloidosis. PATIENTS AND METHODS: We evaluated 87 patients with cardiac amyloidosis who underwent renal technetium-99m-labeled dimercaptosuccinic acid scintigraphy in the Amyloidosis Referral Center of Henri-Mondor Hospital from October 1, 2015, through February 28, 2018. RESULTS: Three groups of patients were identified according to the underlying amyloidosis disorder: AL amyloidosis in 24 patients, mutated-transthyretin amyloidosis in 24 patients, and wild-type transthyretin amyloidosis in 39 patients. Patients with wild-type transthyretin amyloidosis were older (P<.001), more likely to be men (P=.02), to have arrhythmic heart diseases (P<.001), and to be receiving anticoagulation treatment (P<.001). Patients with AL amyloidosis had significantly higher N-terminal pro-B-type natriuretic peptide levels (P=.02) and were more likely to have nephrotic syndrome (P<.001). Renal infarction was detected in 18 patients (20.7%), at similar frequencies in the various groups. Baseline urinary protein to creatinine ratio was the only parameter for which a significant difference (P=.03) was found between patients with and without RI diagnoses. The likelihood of RI diagnosis was 47.1% (8 of 17) in the presence of AKI and 14.5% (10 of 69) in its absence (P=.003). Overall, heart transplant-censored patient survival did not differ significantly between patients with and without RI (P=.64), but death- and heart transplant-censored renal survival was significantly lower in patients with RI (P<.001). CONCLUSION: Our study suggests that prevalence of RI in patients with cardiac amyloidosis is higher than previously thought, regardless of the underlying amyloidosis disorder. Acute kidney injury in a patient with cardiac amyloidosis should alert clinicians to the possibility of RI.

99mTc-HMPAO-leukocyte scintigraphy for diagnosis and therapy monitoring of skull base osteomyelitis.

OBJECTIVE: Skull base osteomyelitis (SBO) is a rare but life-threatening disease observed in elderly diabetic patients, with high risk of recurrence and difficult therapeutic management. The diagnosis is ascertained from a set of clinical, biological, and imaging findings. CT and MRI allow initial diagnosis, but are not accurate to affirm healing at the end of therapy. 99mTc-HMPAO-Leucocyte Scintigraphy (LS) is highly sensitive and specific for the detection of infection. The aim of this study was to evaluate LS i) for initial diagnosis, and ii) to confirm healing at the end of antibiotherapy in SBO. STUDY DESIGN: We retrospectively reviewed from November 2011 to September 2015 all patients with confirmed SBO who underwent LS twice, at diagnosis and at the end of antibiotic therapy in our nuclear medicine department (n = 27). METHODS: Clinical, biological, CT, LS, and follow-up data were recorded in all patients. LS images (planar and tomographic performed 4 hours and 24 hours after intravenous injection of autologous Tc-99m-HMPAO-leucocytes) were visually assessed and quantified. RESULTS: At initial diagnosis, 25 of 27 patients had a positive LS. At the end of antibiotic therapy (3 ± 1 months duration), 26 of 27 patients had a negative LS. During subsequent follow-up (= or >6 months), the disease recurred in four patients including three with a negative postantibiotherapy LS scan. CONCLUSION: In this retrospective study, LS was powerful for initial diagnostic of SBO and for healing assessment at the end of antibiotic therapy. We conclude it is a useful technique for therapeutic monitoring of SBO. LEVEL OF EVIDENCE: 4.

Apical sparing pattern of left ventricular myocardial 99mTc-HMDP uptake in patients with transthyretin cardiac amyloidosis.

BACKGROUND: A decreased longitudinal strain in basal segments with a base-to-apex gradient has been described in patients with cardiac amyloidosis (CA). OBJECTIVES: Aim was to investigate the left ventricular (LV) regional distribution of early-phase 99mTc-Hydroxymethylene diphosphonate (99mTc-HMDP) uptake in patients with transthyretin-related cardiac amyloidosis (TTR-CA). METHODS: All patients underwent a whole-body planar 99mTc-HMDP scintigraphy acquired at 10-min post-injection (early-phase) followed by a thorax SPECT/CT. The segmental uptake (expressed as % of maximal myocardial HMDP uptake) was investigated on the AHA 17-segment model and 3-segment model (basal, mid-cavity, apical). RESULTS: Sixty-one TTR-CA patients were included of whom 29 were wild-type (wt-TTR-CA) and 32 had hereditary TTR-CA (m-TTR-CA). Early myocardial 99mTc-HMDP uptake occurred in all TTR-CA. In all patients, segmental analysis of the LV myocardial distribution of 99mTc-HMDP uptake showed an increased median uptake (interquartile range) in basal/mid-cavity segments compared to the lowest median uptake of apical segments (respectively, 79% [72%-86%] vs. 72% [64%-81%]; P < 10-6). This pattern was similar in wt-TTR-CA group (78% [70%-84%] vs. 70% [61%-81%]; P < 10-6), in m-TTR-CA group (80% [74%-86%] vs. 73 [66%-82%]; P < 10-7) and remained constant independently of the TTR mutation subtype with P ranging 10-5 to 0.03. CONCLUSIONS: Early-phase myocardial scintigraphy identified regional distribution of 99mTc-HMDP uptake characterized by a base-to-apex gradient, corroborating echocardiographic, and cardiac magnetic resonance findings. This apical sparing pattern was similar across TTR-CA and TTR mutation subtypes.

Early-phase myocardial uptake intensity of 99mTc-HMDP vs 99mTc-DPD in patients with hereditary transthyretin-related cardiac amyloidosis.

BACKGROUND: This study sought to compare the intensity of early-phase myocardial uptake of two phosphonate-based radiotracers, 99mTc-hydroxymethylene diphosphonate (HMDP) and 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD), in patients with hereditary transthyretin-related cardiac amyloidosis (TTR-CA). METHODS: Six patients with biopsy-proven diagnosis of TTR-CA and characteristic amyloid fibril composition underwent early-phase 99mTc-HMDP myocardial scintigraphy as part of their routine workup; they were later assessed by 99mTc-DPD scintigraphy after having signed informed written consent. Heart-to-mediastinum-ratio was measured at both time points as well as regional distribution on 17-segment analysis. RESULTS: All patients had an H/M ratio >1.28 on both imaging. 99mTc-DPD uptake was slightly higher than 99mTc-HMDP uptake in 3 patients, but no statistical difference was found (P = 0.13). Regional distribution of the two radiotracers was well correlated on bull's eyes analysis, with only slight underestimation of 99mTc-DPD uptake in the anterior/apical segments, compared with 99mTc-HMDP. CONCLUSION: 99mTc-HMDP and 99mTc-DPD show comparable myocardial uptake intensity on early-phase scintigraphy and can be used alternatively for the diagnosis of TTR-CA.

Predictive value of brain 18F-FDG PET/CT in macrophagic myofasciitis?: A case report.

RATIONALE: Although several functional studies have demonstrated that positron emission tomography/computed tomography with F-fluorodeoxyglucose (F-FDG PET/CT) appears to be efficient to identify a cerebral substrate in patients with known macrophagic myofasciitis (MMF), the predictive value of this imaging technique for MMF remains unclear. PATIENT CONCERNS: We presented data and images of a 46-year-old woman. DIAGNOSES: The patient was referred to our center for suspected MMF due to diffuse arthromyalgias and cognitive disorder (involving an impairment of visual selective attention and a weakness in executive functions revealed by neuropsychological assessment) which occurred few years after last vaccine injections. INTERVENTIONS: After a first negative deltoid muscle biopsy, a brain F-FDG PET/CT was performed and revealed the known spatial pattern of a cerebral glucose hypometabolism involving occipital cortex, medial temporal areas, and cerebellum. OUTCOMES: Given the clinical suspicion of MMF and brain F-FDG PET/CT findings, a 2nd deltoid muscle biopsy was performed and confirmed the diagnosis of MMF with typical histopathological features. LESSONS: This case highlights the predictive value of brain F-FDG PET/CT as a noninvasive imaging tool for MMF diagnosis, even when muscle biopsy result comes back negative.

Cerebral 18F-FDG PET in macrophagic myofasciitis: An individual SVM-based approach.

INTRODUCTION: Macrophagic myofasciitis (MMF) is an emerging condition with highly specific myopathological alterations. A peculiar spatial pattern of a cerebral glucose hypometabolism involving occipito-temporal cortex and cerebellum have been reported in patients with MMF; however, the full pattern is not systematically present in routine interpretation of scans, and with varying degrees of severity depending on the cognitive profile of patients. Aim was to generate and evaluate a support vector machine (SVM) procedure to classify patients between healthy or MMF 18F-FDG brain profiles. METHODS: 18F-FDG PET brain images of 119 patients with MMF and 64 healthy subjects were retrospectively analyzed. The whole-population was divided into two groups; a training set (100 MMF, 44 healthy subjects) and a testing set (19 MMF, 20 healthy subjects). Dimensionality reduction was performed using a t-map from statistical parametric mapping (SPM) and a SVM with a linear kernel was trained on the training set. To evaluate the performance of the SVM classifier, values of sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV) and accuracy (Acc) were calculated. RESULTS: The SPM12 analysis on the training set exhibited the already reported hypometabolism pattern involving occipito-temporal and fronto-parietal cortices, limbic system and cerebellum. The SVM procedure, based on the t-test mask generated from the training set, correctly classified MMF patients of the testing set with following Se, Sp, PPV, NPV and Acc: 89%, 85%, 85%, 89%, and 87%. CONCLUSION: We developed an original and individual approach including a SVM to classify patients between healthy or MMF metabolic brain profiles using 18F-FDG-PET. Machine learning algorithms are promising for computer-aided diagnosis but will need further validation in prospective cohorts.

Brain 18F-FDG PET Metabolic Abnormalities in Patients with Long-Lasting Macrophagic Myofascitis.

The aim of this study was to characterize brain metabolic abnormalities in patients with macrophagic myofascitis (MMF) and the relationship with cognitive dysfunction through the use of PET with 18F-FDG. Methods:18F-FDG PET brain imaging and a comprehensive battery of neuropsychological tests were performed in 100 consecutive MMF patients (age [mean ± SD], 45.9 ± 12 y; 74% women). Images were analyzed with statistical parametric mapping (SPM12). Through the use of analysis of covariance, all 18F-FDG PET brain images of MMF patients were compared with those of a reference population of 44 healthy subjects similar in age (45.4 ± 16 y; P = 0.87) and sex (73% women; P = 0.88). The neuropsychological assessment identified 4 categories of patients: those with no significant cognitive impairment (n = 42), those with frontal subcortical (FSC) dysfunction (n = 29), those with Papez circuit dysfunction (n = 22), and those with callosal disconnection (n = 7). Results: In comparison with healthy subjects, the whole population of patients with MMF exhibited a spatial pattern of cerebral glucose hypometabolism (P < 0.001) involving the occipital lobes, temporal lobes, limbic system, cerebellum, and frontoparietal cortices, as shown by analysis of covariance. The subgroup of patients with FSC dysfunction exhibited a larger extent of involved areas (35,223 voxels vs. 13,680 voxels in the subgroup with Papez circuit dysfunction and 5,453 voxels in patients without cognitive impairment). Nonsignificant results were obtained for the last subgroup because of its small population size. Conclusion: Our study identified a peculiar spatial pattern of cerebral glucose hypometabolism that was most marked in MMF patients with FSC dysfunction. Further studies are needed to determine whether this pattern could represent a diagnostic biomarker of MMF in patients with chronic fatigue syndrome and cognitive dysfunction.