Erdheim-Chester Disease Due to a Novel Internal Duplication of NRAS: Response to Targeted Therapy with Cobimetinib.

Histiocytoses encompass a group of exceptionally rare disorders characterized by the abnormal infiltration of tissues by histocytes. Among these, Erdheim-Chester disease (ECD) stands out as a multisystem histiocytosis that typically affects bones and various other tissues. Historically, the treatment of ECD has been challenging. However, recent breakthroughs in our understanding, particularly the discovery of somatic mutations in the RAS-MAPK pathway, have opened new opportunities for targeted therapy in a significant subset of patients with ECD and other histiocytoses. In this report, we present the case of a patient with ECD harboring a previously unidentified microduplication in the NRAS gene in a small fraction of skin cells. This discovery played a pivotal role in tailoring an effective therapeutic approach involving kinase inhibitors downstream of NRAS. This case underscores the crucial role of deep sequencing of tissue samples in ECD, enabling the delivery of personalized targeted therapy to patients.

Osteomesopyknosis associated with a novel ALOX5 variant that impacts the RANKL pathway.

BACKGROUND: Bone tissue homeostasis relies on the coordinated activity of the bone-forming osteoblasts and bone-resorbing osteoclasts. Osteomesopyknosis is considered a distinctive rare sclerosing skeletal disorder of unelucidated pathophysiology and presumably autosomal dominant transmission. However, the causal genes are unknown. METHODS: We present a case report encompassing clinical assessments, imaging studies, and whole-exome sequencing analysis, complemented by functional in vitro experiments. RESULTS: This new case of osteomesopyknosis was associated with a missense ALOX5 variant predicted to induce protein misfolding and proteasomal degradation. Transfection experiments demonstrated that the variant was associated with reduced protein levels restored by proteasomal inhibition with bortezomib. Likewise, gene expression analysis showed that the mutated gene was associated with a decreased RANKL/OPG ratio, which is a critical driver of osteoclast precursor differentiation. CONCLUSION: Our data indicate impaired bone resorption as the underlying mechanism of this rare osteosclerosis, implicating ALOX5 pathogenic variants as potential etiological factors.

Where Should I Draw the Line: PET-Driven, Data-Driven, or Manufacturer Cut-Off?

Background: The optimal cut-off for Alzheimer's disease (AD) CSF biomarkers remains controversial. Objective: To analyze the performance of cut-off points standardized by three methods: one that optimized the agreement between 11C-Pittsburgh compound B PET (a-PET) and CSF biomarkers (Aß1-42, pTau, tTau, and Aß1-42/Aß1-40 ratio) in our population, called PET-driven; an unbiased cut-off using data from a healthy research cohort, called data-driven, and that provided by the manufacturer. We also compare changes in ATN classification. Methods: CSF biomarkers measured by the LUMIPULSE G600II platform and qualitative visualization of amyloid positron emission tomography (a-PET) were performed in all the patients. We established a cut-off for each single biomarker and Aß1-42/Aß1-40 ratio that optimized their agreement with a-PET using ROC curves. Sensitivity, Specificity, and Overall Percent of Agreement are assessed using a-PET or clinical diagnosis as gold standard for every cut-off. Also, we established a data-driven cut-off from our cognitively unimpaired cohort. We then analyzed changes in ATN classification. Results: One hundred and ten patients were recruited. Sixty-six (60%) were a-PET positive. PET-driven cut-offs were: pTau > 57, tTau > 362.62, Aß1-42/Aß1-40 < 0.069. For a single biomarker, pTau showed the highest accuracy (AUC 0.926). New PET-driven cut-offs classified patients similarly to manufacturer cut-offs (only two patients changed). However, 20 patients (18%) changed when data-driven cut-offs were used. Conclusions: We established our sample's best CSF biomarkers cut-offs using a-PET as the gold standard. These cut-offs categorize better symptomatic subjects than data-driven in ATN classification, but they are very similar to the manufacturer's.

Plasma Phosphorylated Tau 231 Increases at One-Year Intervals in Cognitively Unimpaired Subjects.

Background: Plasma biomarkers of Alzheimer's disease (AD) constitute a non-invasive tool for diagnosing and classifying subjects. They change even in preclinical stages, but it is necessary to understand their properties so they can be helpful in a clinical context. Objective: With this work we want to study the evolution of p-tau231 plasma levels in the preclinical stages of AD and its relationship with both cognitive and imaging parameters. Methods: We evaluated plasma phosphorylated (p)-tau231 levels in 146 cognitively unimpaired subjects in sequential visits. We performed a Linear Mixed-effects Model to analyze their rate of change. We also correlated their baseline levels with cognitive tests and structural and functional image values. ATN status was defined based on cerebrospinal fluid biomarkers. Results: Plasma p-tau231 showed a significant rate of change over time. It correlated negatively with memory tests only in amyloid-positive subjects. No significant correlations were found with any imaging measures. Conclusions: Increases in plasma p-tau231 can be detected at one-year intervals in cognitively healthy subjects. It could constitute a sensitive marker for detecting early signs of neuronal network impairment by amyloid.

Sarcoidosis presenting as transient ischemic attack status.

We report a patient who experienced multiple transient ischemic attacks (TIAs) over a 3-month period as the presenting clinical manifestation of sarcoidosis. This previously healthy 27-year-old man was admitted due to several daily episodes of usually left hemiparesis and dysarthria lasting between 15 seconds and 3 minutes. He did not respond to aggressive antithrombotic treatment. Extensive investigations were negative except for a computed tomography body scan showing several small right hilar lymphoadenopathies, which were confirmed by abnormal 67-gallium scintigraphy and 18F-fluorodeoxyglucose positron emission tomography uptakes. The TIA episodes disappeared after the initiation of prednisone therapy. The lymphadenopathy specimens were biopsied via mediastinoscopy, and histological study revealed noncaseating epithelioid granulomatous inflammation consistent with sarcoidosis. Sarcoidosis should be considered in the differential diagnosis of stroke of unknown origin in any young patient, even in the absence of other clinical or laboratory features of sarcoidosis.

Fluorine-18-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in a Giant Left Pectoral Muscle Plasmacytoma and Multiple Myeloma Case.

Extramedullary plasmacytoma is an unusual manifestation in multiple myeloma (MM). It can present as a solitary bone lesion and/or soft-tissue mass. Plasmacytoma can be presented at any location, but it is more common in the head and neck, usually without systemic involvement. The presence of plasmacytoma in MM is a predictor of rapidly progressive disease. The value of fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (PET-FDG) is increasing, in the diagnosis, detection of occult lesions, and therapeutic monitoring. We describe a patient with rapidly-progressive, refractory, left pectoral muscle plasmacytoma and MM. A PET-FDG guided the therapy and allowed to identify the presence of disease relapse.

A 5-year longitudinal evaluation in patients with mild cognitive impairment by 11C-PIB PET/CT: a visual analysis.

OBJECTIVE: The aim of this study was to evaluate the cerebral amyloid distribution in patients with mild cognitive impairment (MCI), assessed by carbon-11-Pittsburgh compound B (C-PIB) PET/CT, after 5 years of follow-up. PATIENTS AND METHODS: Ten amnestic MCI (A-MCI) and four nonamnestic (NA-MCI) patients were studied by C-PIB PET/CT and re-evaluated 5 years later by a new C-PIB PET/CT. PET/CT scans were acquired 60-90 min after the administration of 555 MBq C-PIB and analyzed visually, to obtain a score of the cerebral cortical C-PIB retention in the frontal, basal ganglia (BG), temporoparietal (TP), occipital, posterior cingulate, and cerebellum areas. Initial and 5-year follow-up C-PIB retentions were compared. RESULTS: Initially, 9/10 A-MCI patients were C-PIB positive and one was C-PIB negative. All four NA-MCI patients were C-PIB negative. Of the C-PIB-positive A-MCI patients, seven progressed to Alzheimer's disease dementia (AD-D), one to mixed dementia and one remained as A-MCI. The C-PIB-negative A-MCI patient remained as A-MCI. Of the four C-PIB-negative NA-MCI, one progressed to semantic dementia. All changes in C-PIB retention were of low intensity. The A-MCI patients who progressed to AD-D (n=7) showed an increase in C-PIB retention in the frontal (5/7), BG (3/7), TP (3/7), occipital (1/7), and posterior cingulate (1/7) regions. The A-MCI patient who progressed to mix dementia showed an increase in C-PIB retention in the frontal region. The C-PIB-positive A-MCI patient who remained as A-MCI showed an increase in C-PIB retention in the frontal, BG, and TP areas. The amyloid deposition in the anterior part of the brain (frontal, TP, and BG) increased more than that in the posterior part (occipital and precuneus) (7/9 vs. 2/9; P<0.05). CONCLUSION: PIB retention increased predominantly in the frontal, BG, and TP areas. C-PIB-positive A-MCI patients mostly progressed to AD-D, showing similar topographic changes in their cerebral C-PIB pattern than the patient who remained as A-MCI.

Effect of positive carbon-11-choline PET/CT results in the therapeutic management of prostate cancer biochemical relapse.

OBJECTIVE: Carbon-11-(C)-choline PET/computed tomography (CT) has shown good results in re-staging of prostate cancer (PCa) with raised serum levels of prostate-specific antigen. Our aim was to evaluate the effect of positive C-choline PET/CT results in the therapeutic management of patients with PCa with biochemical relapse (BR) after curative intention treatment. PATIENTS AND METHODS: A total of 112 patients with PCa BR and positive C-choline PET/CT were retrospectively evaluated. PET/CT was acquired 20 min after intravenous administration of 555-740 MBq of C-choline. The therapeutic management after C-choline PET/CT was obtained from the clinical records. The minimum follow-up time was 18 months. RESULTS: In 80 (71.4%) of 112 patients, C-choline PET/CT showed local recurrence of PCa; in 17 (15.2%) patients, distant recurrence; and in 15 (13.4%) patients, local plus distant recurrence. A second malignancy was detected in five (4.5%) patients. The planned therapeutic management was changed as per positive C-choline PET/CT result in 74 (66.1%) patients and were treated as follows: 31 (27.7%) patients with HT, combined with other treatments in eight (7.1%), 17 (15.2%) with BT, 13 (11.6%) with external beam radiotherapy, one (0.9%) with RP, and four (3.6%) with chemotherapy. Treatment approach was not modified in 37 (33%) patients. No data was available from one (0.9%) patient. CONCLUSION: Positive C-choline PET/CT result had an important effect in the therapeutic management of patients with PCa and BR, leading to a change in the planned approach in two (66.1%) out of three patients. In addition, in 4.5% of the patients, the C-choline PET/CT allowed the detection of a second malignancy.

18F-FDG PET/CT in the follow-up of large-vessel vasculitis: A study of 37 consecutive patients.

OBJECTIVE: 18F-FDG PET/CT has proved to be of potential value for early diagnosis of large-vessel vasculitis (LVV), which frequently involves the aorta. However, its role in the follow-up of these patients has not been well established. Our aim was to evaluate the contribution of 18F-FDG PET/CT in this clinical situation. METHODS: This study included 37 consecutive patients (28 women, 66.5 ± 9.9 years) with an initial 18F-FDG PET/CT positive for LVV and a mean ± standard deviation follow-up PET/CT of 7.5 ± 2.9 months after the initial scan. A semiquantitative analysis of aortic wall uptake was performed calculating the target-to-background ratio (TBR: aortic wall uptake divided by blood pool uptake). The initial and follow-up TBR as well as the clinical and laboratory outcome were compared. RESULTS: Overall, the mean TBR decreased from 1.7 ± 0.5 at the initial scan to 1.5 ± 0.3 at the time of follow-up (p = 0.0001). In the 21 patients who experienced clinical improvement following therapy the TBR also decreased from 1.8 ± 0.6 to 1.5 ± 0.3 (p = 0.0002). However, in the other 16 patients, in whom the treating physician considered that there was no clinical improvement following therapy, no statistically significant differences in TBR were found when data from the first and the follow-up PET/CT scans were compared (1.6 ± 0.3 versus 1.5 ± 0.3, p = 0.1416). Patients who experienced clinical improvement following therapy showed a nonstatistically significant higher TBR at the time of disease diagnosis (1.8 ± 0.6 versus 1.6 ± 0.3; p = 0.12). CONCLUSIONS: The results obtained in the present study highlight the impact of 18F-FDG PET/CT on the management of patients with LVV.

Utility of Amyloid and FDG-PET in Clinical Practice: Differences Between Secondary and Tertiary Care Memory Units.

The clinical utility of amyloid positron emission tomography (PET) has not been fully established. Our aim was to evaluate the effect of amyloid imaging on clinical decision making in a secondary care unit and compare our results with a previous study in a tertiary center following the same methods. We reviewed retrospectively 151 cognitively impaired patients who underwent amyloid (Pittsburgh compound B [PiB]) PET and were evaluated clinically before and after the scan in a secondary care unit. One hundred and fifty concurrently underwent fluorodeoxyglucose (FDG)-PET. We assessed changes between the pre- and post-PET clinical diagnosis and Alzheimer's disease treatment plan. The association between PiB/FDG results and changes in management was evaluated using χ2 and multivariate logistic regression. Concordance between classification based on scan readings and baseline diagnosis was 66% for PiB and 47% for FDG. The primary diagnosis changed after PET in 17.2% of cases. When examined independently, discordant PiB and discordant FDG were both associated with diagnostic change (p < 0.0001). However, when examined together in a multivariate logistic regression, only discordant PiB remained significant (p = 0.0002). Changes in treatment were associated with concordant PiB (p = 0.009) while FDG had no effect on treatment decisions. Based on our regression model, patients with diagnostic dilemmas, a suspected non-amyloid syndrome, and Clinical Dementia Rating <1 were more likely to benefit from amyloid PET due to a higher likelihood of diagnostic change. We found that changes in diagnosis after PET in our secondary center almost doubled those of our previous analysis of a tertiary unit (9% versus 17.2%). Our results offer some clues about the rational use of amyloid PET in a secondary care memory unit stressing its utility in mild cognitive impairment patients.

Diagnosis of common iliac artery thrombosis and renal artery thrombosis in a kidney transplant by radionuclide renography.

In a 58-year-old woman, the external iliac artery was accidentally dissected during the arterial anastomosis of a kidney transplant. An immediate CT angiogram showed an almost total occlusion of the common iliac artery. After the transplantation, radionuclide renography with Tc-99m MAG3 showed no flow across the right common iliac artery and no graft vascularization. Sequential images showed a photopenic area corresponding to the renal graft. These findings were interpreted as common iliac artery thrombosis and renal artery thrombosis associated with renal graft infarct. Excision of the transplant and iliofemoral bypass were performed. Pathologic examination of the graft showed massive acute renal infarct and renal artery thrombosis.

In-111 ibritumomab scintigraphy (planar and SPECT) and FDG PET/CT before Y-90 ibritumomab treatment in a patient with mantle cell lymphoma.

We report the case of a 75-year-old man, in whom Y-90 ibritumomab was requested because of relapse of blastoid variant mantle cell lymphoma diagnosed in 1995. Before Y-90 ibritumomab treatment, FDG PET and In-111 ibritumomab scintigraphy with planar views at 24 hours, 48 hours, and 5 days, including SPECT, were performed. Discordant information between both examinations was observed as, in addition to the lesions detected by In-111 ibritumomab imaging, FDG PET detected lesions that did not take up the ibritumomab. The discrepancy shown by both radiotracers has to be kept in mind before planning treatment with Y-90 ibritumomab, and for the correct evaluation of treatment response.

Erythema Nodosum-Like Panniculitis as a False-Positive 18F-FDG PET/CT in Advanced Melanoma Treated With Dabrafenib and Trametinib.

We present a 35-year-old woman with left axillary mass. Histopathological analysis revealed metastatic infiltration for BRAF-mutant melanoma. F-FDG PET/CT showed bilateral axillary lymphadenopathy as well as bone and subcutaneous metastases. Dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) combined therapy was started with a complete metabolic response established by 2 consecutive PET/CT scans. A follow-up PET/CT showed FDG uptake in several subcutaneous nodules in both distal legs, suggesting metastases. Painless cutaneous lesions were observed on physical examination, and biopsy revealed erythema nodosum-like panniculitis.

Value of the visual and semiquantitative analysis of carbon-11-methionine PET/CT in brain tumors' recurrence versus post-therapeutic changes.

To compare the visual and semiquantitative analysis of carbon-11-methionine (C-MET) PET/computed tomography (CT) images in patients with primary brain tumors and suspected recurrence, persistence, or necrotic post-therapeutic changes. A total of 41 consecutive C-MET-PET/CT scans on 35 (21 men, mean age 44.1±16.6 years) patients were requested for MRI suspicion of recurrent or persistent primary tumor after therapy. The C-MET PET/CT were obtained 20 min after an intravenous injection of 555-740 MBq (15-20 mCi) of C-MET. Both visual and semiquantitative evaluations were performed comparing C-MET uptake between suspicious areas and different lesion/normal-to-background ratios. The final diagnosis was established by histological examination in 12 cases and clinical and MRI follow-up in 29 cases. Visual analyses were positive in 27 (63.4%) and negative in 14 (36.6%) of the C-MET PET/CT. The sensitivity was 83.9%, specificity was 90.0%, positive predictive value was 96.3%, negative predictive value was 64.3% and accuracy was 71.4%. For the semiquantitative analysis, all the lesion/normal-to-background ratios could differentiate between tumor and nontumor (P<0.001), the lesion/contralateral parenchyma (L/CP) maximum standardized uptake value (SUVmax) being the index with the highest area under de curve (0.938). Applying an L/CP SUVmax index of 1.21, the sensitivity was 89.3%, specificity was 90.0%, positive predictive value was 96.1%, negative predictive value was 75%, and accuracy was 82.9%. C-MET-PET/CT was a useful technique to differentiate post-therapeutic changes from tumor presence in treated patients with brain neoplasm in whom cerebral MRI is nonconclusive, showing a high diagnostic performance. Our results showed only slight differences between visual analysis methods and the L/CP SUVmax ratio, the best of the semiquantitative methods.

Amyloid Imaging With 11C-PIB in Patients With Cognitive Impairment in a Clinical Setting: A Visual and Semiquantitative Analysis.

PURPOSE: The aim of this study was to evaluate amyloid imaging with 11C-PIB PET/CT in the study of cognitive impairment in a clinical setting. PATIENTS AND METHODS: The study included 64 patients, with a mean age of 65 years, classified as subjective memory complaints (SMCs; n = 8), nonamnestic mild cognitive impairment (NA-MCI; n = 10), amnestic MCI (A-MCI; n = 19), prodromal Alzheimer disease (AD; n = 12), suspicion of frontotemporal dementia (n = 8), Lewy bodies dementia (DLB; n = 2), and cortical degeneration (CD; n = 5). Ten healthy controls (HCs), with a mean age of 59 years, were also included. 11C-PIB was acquired 60 minutes after IV injection of 555 MBq 11C-PIB. A visual and semiquantitative analysis was performed. RESULTS: In HC, 11C-PIB was negative in 9 and positive in 1. Of the 64 patients, 11C-PIB was negative in 27 (42%) and positive in 37 (58%). 11C-PIB was positive in 3 of 8 SMC, in none of 10 NA-MCI, in 14 of 19 A-MCI, in 10 of 12 prodromal AD, in 3 of 8 frontotemporal dementia, and in the 2 and 5 DLB and CD patients. The semiquantitative results in terms of mean global SUV ratio were 1.13 for HC, 1.36 for SMC, 1.07 for NA-MCI, 2.01 for A-MCI, 2.37 for prodromal AD, 2.75 for DLB, and 2.44 for CD. CONCLUSIONS: In a clinical setting, 11C-PIB scan had a relevant contribution on patients with cognitive impairment, excluding AD in a high proportion of MCI patients and differentiating AD from other dementias. In A-MCI, 11C-PIB revealed ß-amyloid deposit in 74%, whereas it was negative in all NA-MCI patients.

The Role of PET/CT Molecular Imaging in the Diagnosis of Recurrence and Surveillance of Patients Treated for Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide and its prognosis remains poor. Molecular imaging with 18F-FDG PET/CT can metabolically characterize the nature of lesions as benign or malignant, allowing a better staging at the diagnosis of this kind of patient. This advantage can also be applied in the re-staging due to the suspicion of recurrent disease. Many patients have a recurrence of the disease, including surgically treated patients. In the current context, with new personalized oncological treatments, the surveillance for recurrence and its accurate diagnosis are crucial to improve their survival. In this paper, we revise the current knowledge about the clinical and molecular factors related to the recurrent disease. In the context of new, promising, available personalized treatments, the role of molecular imaging with PET/CT and 18F-FDG and non-18F-FDG radiotracers in the follow-up of NSCLC-treated patients is especially attractive and interesting.

Diagnostic role of 11C-Pittsburgh compound B retention patterns and glucose metabolism by fluorine-18-fluorodeoxyglucose PET/CT in amnestic and nonamnestic mild cognitive impairment patients.

OBJECTIVE: Amyloid imaging clinically is usually reported as positive or negative, and the role of amyloid topography has not been studied before. To evaluate in a clinical setting the regional distribution patterns of C-Pittsburgh compound B (C-PIB) and the fluorine-18-fluorodeoxyglucose (F-FDG) uptake in patients with mild cognitive impairment (MCI), we designed this study. METHODS: We studied 81 consecutive MCI patients, 64 amnestic (A-MCI) and 17 nonamnestic (NA-MCI) by C-PIB and F-FDG PET/computed tomography, by visual analysis. PIB retention was classified according to the regional distribution into the following patterns: A (frontal, lateral temporal, basal ganglia and anterior cingulate) and B (global retention). F-FDG images were considered positive only if temporoparietal hypometabolism consistent with Alzheimer's disease was observed. RESULTS: In 42 of the 64 A-MCI, C-PIB was positive. Twelve of the 42 positive A-MCI showed an A-pattern, all F-FDG negative, and 30 a B-pattern, 10 F-FDG positive and 20 F-FDG negative. Of the 17 NA-MCI, C-PIB was positive in three and F-FDG was positive in one. The different proportion of C-PIB positivity in A-MCI and NA-MCI was highly significant (P<0.001). CONCLUSION: Two different C-PIB patterns were observed in MCI patients and for the A-pattern, glucose hypometabolism consistent with Alzheimer's disease is highly unlikely. These findings may contribute towards a better selection of patients for future potential treatments and also to optimize the use of F-FDG-PET/CT.

Bilateral adrenocortical uptake of Ga-67 SPECT during septicemia in a heart transplant patient.

Gallium-67 scintigraphy is a valuable agent in the management of fever of unknown origin. The use of SPECT increases its sensitivity and may demonstrate unexpected findings. We report on a heart-transplanted 55-year-old man with postsurgical fever of unknown origin. Ga-67 SPECT showed bilateral abnormal adrenal gland uptake that disappeared after intensive antibiotic therapy as assessed by a new Ga-67 scintigraphy obtained 3 months later. Unilateral and bilateral adrenal uptake of gallium has been reported in several clinical settings, ranging from adrenocortical adenomas to malignant disease such as lymphoma or adrenal metastases. Only one similar case, septicemia with transient adrenal uptake of gallium, has been previously reported.