Semi-quantitative Measurements Research Articles

Brain and Ventricle Volume Alterations in Idiopathic Normal Pressure Hydrocephalus Determined by Artificial Intelligence-Based MRI Volumetry

The aim of this study was to employ artificial intelligence (AI)-based magnetic resonance imaging (MRI) brain volumetry to potentially distinguish between idiopathic normal pressure hydrocephalus (iNPH), Alzheimer’s disease (AD), and age- and sex-matched healthy controls (CG) by evaluating cortical, subcortical, and ventricular volumes. Additionally, correlations between the measured brain and ventricle volumes and two established semi-quantitative radiologic markers for iNPH were examined. An IRB-approved retrospective analysis was conducted on 123 age- and sex-matched subjects (41 iNPH, 41 AD, and 41 controls), with all of the iNPH patients undergoing routine clinical brain MRI prior to ventriculoperitoneal shunt implantation. Automated AI-based determination of different cortical and subcortical brain and ventricular volumes in mL, as well as calculation of population-based normalized percentiles according to an embedded database, was performed; the CE-certified software mdbrain v4.4.1 or above was used with a standardized T1-weighted 3D magnetization-prepared rapid gradient echo (MPRAGE) sequence. Measured brain volumes and percentiles were analyzed for between-group differences and correlated with semi-quantitative measurements of the Evans’ index and corpus callosal angle: iNPH patients exhibited ventricular enlargement and changes in gray and white matter compared to AD patients and controls, with the most significant differences observed in total ventricular volume (+67%) and the lateral (+68%), third (+38%), and fourth (+31%) ventricles compared to controls. Global ventriculomegaly and marked white matter reduction with concomitant preservation of gray matter compared to AD and CG were characteristic of iNPH, whereas global and frontoparietally accentuated gray matter reductions were characteristic of AD. Evans’ index and corpus callosal angle differed significantly between the three groups and moderately correlated with the lateral ventricular volumes in iNPH patients [Evans’ index (r > 0.83, p ≤ 0.001), corpus callosal angle (r < −0.74, p ≤ 0.001)]. AI-based MRI volumetry in iNPH patients revealed global ventricular enlargement and focal brain atrophy, which, in contrast to healthy controls and AD patients, primarily involved the supratentorial white matter and was marked temporomesially and in the midbrain, while largely preserving gray matter. Integrating AI volumetry in conjunction with traditional radiologic measures could enhance iNPH identification and differentiation, potentially improving patient management and therapy response assessment.

Neuropathological assessment of the olfactory bulb and tract in individuals with COVID-19

The majority of patients with Parkinson disease (PD) experience a loss in their sense of smell and accumulate insoluble α-synuclein aggregates in their olfactory bulbs (OB). Subjects affected by a SARS-CoV-2-linked illness (COVID-19) also frequently experience hyposmia. We previously postulated that microglial activation as well as α-synuclein and tau misprocessing can occur during host responses following microbial encounters. Using semiquantitative measurements of immunohistochemical signals, we examined OB and olfactory tract specimens collected serially at autopsies between 2020 and 2023. Deceased subjects comprised 50 adults, which included COVID19 + patients (n = 22), individuals with Lewy body disease (e.g., PD; dementia with Lewy bodies (n = 6)), Alzheimer disease (AD; n = 3), and other neurodegenerative disorders (e.g., progressive supranuclear palsy (n = 2); multisystem atrophy (n = 1)). Further, we included neurologically healthy controls (n = 9), and added subjects with an inflammation-rich brain disorder as neurological controls (NCO; n = 7). When probing for microglial and histiocytic reactivity in the anterior olfactory nuclei (AON) by anti-CD68 immunostaining, scores were consistently elevated in NCO and AD cases. In contrast, microglial signals on average were not significantly altered in COVID19 + patients relative to healthy controls, although anti-CD68 reactivity in their OB and tracts declined with progression in age. Mild-to-moderate increases in phospho-α-synuclein and phospho-tau signals were detected in the AON of tauopathy- and synucleinopathy-afflicted brains, respectively, consistent with mixed pathology, as described by others. Lastly, when both sides were available for comparison in our case series, we saw no asymmetry in the degree of pathology of the left versus right OB and tracts. We concluded from our autopsy series that after a fatal course of COVID-19, microscopic changes in the rostral, intracranial portion of the olfactory circuitry -when present- reflected neurodegenerative processes seen elsewhere in the brain. In general, microglial reactivity correlated best with the degree of Alzheimer’s-linked tauopathy and declined with progression of age in COVID19 + patients.

Associations of Urine and Plasma Metabolites with Kidney Failure and Death in a CKD Cohort

Rationale & ObjectiveBiomarkers that enable better identification of persons with chronic kidney disease (CKD) who are at higher risk for disease progression and adverse events are needed. This study sought to identify urine and plasma metabolites associated with progression of kidney disease. Study DesignProspective metabolome-wide association study. Setting & ParticipantsPersons with CKD enrolled in the German CKD Study (GCKD) with metabolite measurements; with external validation within the Atherosclerosis Risk in Communities Study. Exposures1,513 urine and 1,416 plasma metabolites (Metabolon, Inc.) measured at study entry using untargeted mass spectrometry. OutcomesMain endpoints were kidney failure (KF), and a composite endpoint of KF, eGFR <15 mL/min/1.73m2, or 40% decline in eGFR (CKE). Death from any cause was a secondary endpoint. After a median of 6.5 years follow-up, 500 persons experienced KF, 1,083 experienced CKE and 680 died. Analytical ApproachTime-to-event analyses using multivariable proportional hazard regression models in a discovery-replication design, with external validation. Results5,088 GCKD participants were included in analyses of urine metabolites and 5,144 in analyses of plasma metabolites. Among 182 unique metabolites, 30 were significantly associated with KF, 49 with CKE, and 163 with death. The strongest association with KF was observed for plasma hydroxyasparagine (hazard ratio: 1.95, 95% confidence interval: 1.68-2.25). An unnamed metabolite measured in plasma and urine was significantly associated with KF, CKE, and death. External validation of the identified associations of metabolites with KF or CKE revealed direction-consistency for 88% of observed associations. Selected associations of 18 metabolites with study outcomes have not been previously reported. LimitationsUse of observational data and semi-quantitative metabolite measurements at a single time point. ConclusionsThe observed associations between metabolites and KF, CKE or death in persons with CKD confirmed previously reported findings and also revealed several associations not previously described. These findings warrant confirmatory research in other study cohorts.

11C-CFT PET brain imaging in Parkinson’s disease using a total-body PET/CT scanner

PurposeThis study aimed to evaluate the feasibility of 11C-CFT PET brain imaging in Parkinson’s Disease using a total-body PET/CT scanner and explore the optimal scan duration to guide the clinical practice.MethodsThirty-two patients with Parkinson’s disease (PD) performing 11C-CFT PET/CT brain imaging using a total-body PET/CT scanner were retrospectively enrolled. The PET data acquired over a period of 900 s were reconstructed into groups of different durations: 900-s, 720-s, 600-s, 480-s, 300-s, 180-s, 120-s, 60-s, and 30-s (G900 to G30). The subjective image quality analysis was performed using 5-point scales. Semi-quantitative measurements were analyzed by SUVmean and dopamine transporter (DAT) binding of key brain regions implicated in PD, including the caudate nucleus and putamen. The full-time images (G900) were served as reference.ResultsThe overall G900, G720, and G600 image quality scores were 5.0 ± 0.0, 5.0 ± 0.0, and 4.9 ± 0.3 points, respectively, and there was no significant difference among these groups (P > 0.05). A significant decrease in these scores at durations shorter than 600 s was observed when compared to G900 images (P < 0.05). However, all G300 image quality was clinically acceptable (≥ 3 points). As the scan duration reduced, the SUVmean and DAT binding of caudate nucleus and putamen decreased progressively, while there were no statistically significant variations in the SUVmean of the background among the different groups. Moreover, the changes in the lesion DAT binding (ΔDAT-binding) between the full-time reference G900 image and other reconstructed group G720 to G30 images generally increased along with the reduced scan time.ConclusionSufficient image quality and lesion conspicuity could be achieved at 600-s scan duration for 11C-CFT PET brain imaging in PD assessment using a total-body PET/CT scanner, while the image quality of G300 was acceptable to meet clinical diagnosis, contributing to improve patient compliance and throughput of PET brain imaging.

Phytosterols in human serum as measured using a liquid chromatography tandem mass spectrometry

Phytosterols are lipophilic compounds found in plants with structural similarity to mammalian cholesterol. They cannot be endogenously produced by mammals and therefore always originate from diet. There has been increased interest in dietary phytosterols over the last few decades due to their association with a variety of beneficial health effects including low-density lipoprotein cholesterol lowering, anti-inflammatory and anti-cancerous effects. They are proposed as potential moderators for diseases associated with the central nervous system where cholesterol homeostasis is found to be imperative (multiple sclerosis, dementia, etc.) due to their ability to reach the brain. Here we utilised an enzyme-assisted derivatisation for sterol analysis (EADSA) in combination with a liquid chromatography tandem mass spectrometry (LC-MSn) to characterise phytosterol content in human serum. As little as 100 fg of plant sterol was injected on a reversed phase LC column. The method allows semi-quantitative measurements of phytosterols and their derivatives simultaneously with measurement of cholesterol metabolites. The identification of phytosterols in human serum was based on comparison of their LC retention times and MS2, MS3 spectra with a library of authentic standards. Free campesterol serum concentration was in the range from 0.30-4.10 µg/mL, β-sitosterol 0.16-3.37 µg/mL and fucosterol was at lowest concentration range from 0.05-0.38 µg/mL in ten individuals. This analytical methodology could be applied to the analysis of other biological fluids and tissues.

Semiquantitative 18F-FDG PET/CT in monitoring glucocorticoid response of immunoglobulin G4-related effusive constrictive pericarditis: a case report

BackgroundImmunoglobulin G4 (IgG4)-related effusive constrictive pericarditis (ECP) is a rare manifestation of IgG4-related disease (IgG4-RD). It can lead to persistent pericardial fibrosis, resulting in cardiac tamponade, diastolic dysfunction, and heart failure. Glucocorticoids are the primary treatment for effectively reducing inflammation and preventing fibrosis. However, guidelines for monitoring treatment response are lacking and tapering glucocorticoid therapy for specific target organs remains a challenge. Recent studies on IgG4-RD have demonstrated that semiquantitative measurements of fluorine-18 fluorodeoxyglucose (18F-FDG) uptake in the main involved organs in positron emission tomography/computed tomography (PET/CT) scanning are correlated to disease activity. We present a case of IgG4-related ECP to demonstrate the usefulness of 18F-FDG PET/CT for diagnosing and treatment follow-up of IgG4-related ECP.Case presentationHerein, a 66-year-old woman diagnosed with IgG4-related ECP presented with breathlessness, leg swelling, rales, and fever. Laboratory tests revealed markedly elevated levels of C-reactive protein, and transthoracic echocardiography revealed constrictive physiology with effusion. High IgG4 levels suggested an immune-related pathogenesis, while viral and malignant causes were excluded. Subsequent pericardial biopsy revealed lymphocyte and plasma cell infiltration in the pericardium, confirming the diagnosis of IgG4-related ECP. 18F-FDG PET/CT revealed increased uptake of 18F-FDG in the pericardium, indicating isolated cardiac involvement of IgG4-RD. Treatment with prednisolone and colchicine led to a rapid improvement in the patient’s condition within a few weeks. Follow-up imaging with 18F-FDG PET/CT after 3 months revealed reduced inflammation and improved constrictive physiology on echocardiography, leading to successful tapering of the prednisolone dose and discontinuation of colchicine.ConclusionThe rarity of IgG4-related ECP and possibility of multiorgan involvement in IgG4-RD necessitates a comprehensive diagnostic approach and personalized management. This case report highlights the usefulness of 18F-FDG PET/CT in the diagnosis and treatment follow-up of isolated pericardial involvement in IgG4-RD.

High-Throughput Lipidomic and Metabolomic Profiling for Brain Tissue and Biofluid Samples in Neurodegenerative Disorders.

Recent research has revealed the potential of lipidomics and metabolomics in identifying new biomarkers and mechanistic insights for neurodegenerative disorders. To contribute to this promising area, we present a detailed protocol for conducting an integrated lipidomic and metabolomic profiling of brain tissue and biofluid samples. In this method, a single-phase methanol extraction is employed for extracting both nonpolar and highly polar lipids and metabolites from each biological sample. The extracted samples are then subjected to liquid chromatography-mass spectrometry-based assays to provide relative or semiquantitative measurements for hundreds of selected lipids and metabolites per sample. This high-throughput approach enables the generation of new hypotheses regarding the mechanistic and functional significance of lipid and metabolite alterations in neurodegenerative disorders while also facilitating the discovery of new biomarkers to support drug development.

A novel approach to guide GD2-targeted therapy in pediatric tumors by PET and [64Cu]Cu-NOTA-ch14.18/CHO.

Background: The tumor-associated disialoganglioside GD2 is a bona fide immunotherapy target in neuroblastoma and other childhood tumors, including Ewing sarcoma and osteosarcoma. GD2-targeting antibodies proved to be effective in neuroblastoma and GD2-targeting chimeric antigen receptors (CAR)- expressing T cells as well as natural killer T cells (NKTs) are emerging. However, assessment of intra- and intertumoral heterogeneity has been complicated by ineffective immunohistochemistry as well as sampling bias in disseminated disease. Therefore, a non-invasive approach for the assessment and visualization of GD2 expression in-vivo is of upmost interest and might enable a more appropriate treatment stratification. Methods: Recently, [64Cu]Cu-NOTA-ch14.18/CHO (64Cu-GD2), a radiolabeled GD2-antibody for imaging with Positron-Emission-Tomography (PET) was developed. We here report our first clinical patients' series (n = 11) in different pediatric tumors assessed with 64Cu-GD2 PET/MRI. GD2-expression in tumors and tissue uptake in organs was evaluated by semiquantitative measurements of standardized uptake values (SUV) with PET/MRI on day 1 p.i. (n = 11) as well as on day 2 p.i. (n = 6). Results: In 8 of 9 patients with suspicious tumor lesions on PET/MRI at least one metastasis showed an increased 64Cu-GD2 uptake and a high tracer uptake (SUVmax > 10) was measured in 4 of those 8 patients. Of note, sufficient image quality with high tumor to background contrast was readily achieved on day 1. In case of 64Cu-GD2-positive lesions, an excellent tumor to background ratio (at least 6:1) was observed in bones, muscles or lungs, while lower tumor to background contrast was seen in the spleen, liver and kidneys. Furthermore, we demonstrated extensive tumor heterogeneity between patients as well as among different metastatic sites in individual patients. Dosimetry assessment revealed a whole-body dose of only 0.03 mGy/MBq (range 0.02-0.04). Conclusion: 64Cu-GD2 PET/MRI enables the non-invasive assessment of individual heterogeneity of GD2 expression, which challenges our current clinical practice of patient selection, stratification and immunotherapy application scheme for treatment with anti-GD2 directed therapies.

Tectonic-sedimentary evolution in a Palaeocene rifted Lishui Sag, East China Sea Shelf Basin

Influenced by episodic tectonic activity and multiple sediment sources, the source-to-sink systems in rifted basins are relatively complex. Based on seismic data, well logging, cores, thin sections, and heavy mineral data, the growth and linkage of the Lingfeng fault were reconstructed and its influence on the sedimentary responses of the Palaeocene-rifted Lishui Sag in the East China Sea Shelf Basin was examined. The researchers conducted a fault throw-distance analysis on the Lingfeng fault and found that it displayed an overall weak-strong-weak evolutionary process. During the early syn-rift stage, the Lingfeng fault exhibited a segmented geometry consisting of seven fault segments with low fault activity along its strike, and small-scale source-to-sink systems developed in both the hanging wall dip-slope and footwall. As the main syn-rift stage progressed, strong fault activity induced large-scale exposure of the source area, resulting in a high sediment-supply rate and large-scale source-to-sink systems. During the late syn-rift stage, the fault weakened and evolved into a connected basin-boundary fault, and proximal source-to-sink systems in the footwall gradually disappeared. Semi-quantitative measurements of the geomorphic parameters of these source-to-sink systems indicated wide and shallow sediment transport pathways in hanging wall dip-slope areas (average width and depth of approximately 6.34 kmand 0.13 km, respectively) and narrow and deep sediment transport pathways in the footwall (average width and depth of approximately 3.75 km and 0.15 km, respectively). The semi-quantitative statistical analysis implies that the cross-sectional area of the transport channels was positively correlated with the corresponding fan/delta complexes in a rift basin.

Duvelisib for Critically Ill Patients With Coronavirus Disease 2019: An Investigator-Initiated, Randomized, Placebo-Controlled, Double-Blind Pilot Trial.

Despite improvements in prevention and treatment, severe coronavirus disease 2019 (COVID-19) is associated with high mortality. Phosphoinositide 3-kinase (PI3K) pathways contribute to cytokine and cell-mediated lung inflammation. We conducted a randomized, placebo-controlled, double-blind pilot trial to determine the feasibility, safety, and preliminary activity of duvelisib, a PI3Kδγ inhibitor, for the treatment of COVID-19 critical illness. We enrolled adults aged ≥18 years with a primary diagnosis of COVID-19 with hypoxic respiratory failure, shock, and/or new cardiac disease, without improvement after at least 48 hours of corticosteroid. Participants received duvelisib (25 mg) or placebo for up to 10 days. Participants had daily semi-quantitative viral load measurements performed. Dose modifications were protocol driven due to adverse events (AEs) or logarithmic change in viral load. The primary endpoint was 28-day overall survival (OS). Secondary endpoints included hospital and intensive care unit length of stay, 60-day OS, and duration of critical care interventions. Safety endpoints included viral kinetics and AEs. Exploratory endpoints included serial cytokine measurements and cytometric analysis. Fifteen patients were treated in the duvelisib cohort, and 13 in the placebo cohort. OS at 28 days was 67% (95% confidence interval [CI], 38%-88%) compared to 62% (95% CI, 32%-86%) for placebo (P = .544). Sixty-day OS was 60% versus 46%, respectively (hazard ratio, 0.66 [95% CI, .22-1.96]; P = .454). Other secondary outcomes were comparable. Duvelisib was associated with lower inflammatory cytokines. In this pilot study, duvelisib did not significantly improve 28-day OS compared to placebo for severe COVID-19. Duvelisib appeared safe in this critically ill population and was associated with reduction in cytokines implicated in COVID-19 and acute respiratory distress syndrome, supporting further investigation. NCT04372602.

A flexible gradient lateral flow immunochromatographic assay for qualitative, semi-quantitative, and quantitative determination of serum amyloid A

Serum amyloid A (SAA) is an acute-phase protein produced in response to inflammatory proteins during infections, inflammation, trauma, surgery, cancer, and other conditions. Early and accurate detection of SAA is necessary for diagnosis and monitoring of disease progression. To meet this need, we developed a gradient lateral flow immunoassay test strip using Au nanoparticles as signal reporters. The test strip has three test (T1, T2, and T3) lines with progressively decreasing concentrations of SAA antibody, enabling the determination of high, medium, and low concentrations of SAA in serum. The test strip results were analyzed using three distinct readout methods, each with different sensitivity, accuracy, and precision for SAA concentration measurements. Qualitative judgment is based on the color of the T1 line. Semi-quantitative assessment of SAA concentration is determined by the number of colored T-lines. Specifically, color development in T1 line alone indicates a concentration range of 10–50 μg/mL, while T1 and T2 lines together indicate a range of 50–100 μg/mL, and development in all three lines (T1, T2, and T3) indicates a concentration of >100 μg/mL. Quantitative analysis was performed using either smartphone imaging or image scanning with ImageJ software. By using a five-parameter logistic function, we found a strong correlation (R2 = 0.998) between the ratio of signal intensities of (T1 + T2 + T3) to the control (C) line and SAA concentrations ranging from 5 to 1000 μg/mL. At lower concentrations (0–100 μg/mL), we observed a proportional relationship between the value of (T1 + T2 + T3)/C and SAA concentration. The limit of detection for SAA was 9.33 ng/mL (or 6.53 μg/mL of SAA in undiluted serum samples) for the smartphone method and 3.06 ng/mL (or 2.14 μg/mL of SAA in undiluted serum samples) for the scanner method. The gradient test strip was highly consistent with a commercially available SAA immunochromatographic test strip when tested with real human serum samples. Passing-Bablok regression indicated that results obtained using the smartphone app and scanner methods of the gradient test strip were comparable to those obtained using the commercial test strip. The gradient test strip is flexible and adaptable, providing solutions for qualitative, semi-quantitative, and quantitative SAA measurements.

Can lung semi-quantitative measurements and mediastinal adipose tissue volume predict prognosis in patients with idiopathic pulmonary fibrosis (IPF)? A CT-based preliminary study.

The aim of this study was to assess the potential of subcutaneous adipose tissue volume, mediastinal adipose tissue volume, lung density, and lung volume (as measured on high-resolution computed tomography) to predict disease progression in patients with idiopathic pulmonary fibrosis (IPF). Additionally, the study aimed to evaluate the changes in these semiquantitative measures over time. The HRCT images of 57 patients diagnosed with IPF were retrospectively screened. Subcutaneous adipose tissue volume, mediastinal adipose tissue volume, and mean lung density and volume were measured at the time of diagnosis and at the 12th month. The ability of these parameters to predict progression was evaluated using the univariate and multivariate Cox regression analyses. Low mediastinal adipose tissue volume at diagnosis had a 0.991-fold effect [odds ratio (OR)= 0.991, 95% confidence interval (CI)= 0.984-0.997, p< 0.001] on progression. Low mediastinal adipose tissue volume at diagnosis had a 0.993-fold effect [odds ratio (OR)= 0.993, 95% confidence interval (CI)= 0.975-1.011, p< 0.001] and progression development at the 12th month had a 6.5-fold effect [odds ratio (OR)= 6.516, 95% confidence interval (CI)= 1.594-26.639, p< 0.009] on mortality. This study indicate that the prognosis was better in those with a large mediastinal adipose tissue volume among the patients with IPF.

Arterial spin-labeled magnetic resonance perfusion imaging in prediction of pediatric brain tumors grading: inter-observer agreement

BackgroundPediatric brain tumors are a major concern with many variable management options. Arterial spin-labeled magnetic resonance perfusion imaging is a relatively new and noninvasive technique that can help in predicting tumor grades and provide us with physiological data about the tumors which significantly aids in all stages of tumor care, including diagnosis, therapy, and follow-up.Aim of the studyTo determine agreement between independent observers in the assessment and prediction of brain tumor grading in pediatrics by arterial spin-labeled (ASL) magnetic resonance perfusion imaging.MethodsThirty-two patients (21 boys and 11 girls; mean age of (10.28 ± 4.31) years) with brain tumors were evaluated by ASL MRI perfusion. Image analysis was performed by two reviewers for quantifying absolute and relative tumoral blood flow (aTBF and rTBF) as well as qualitative assessment of the tumors in ASL color map images.ResultsThe inter-observer agreement for the mean aTBF and the mean rTBF values of the studied lesions was almost perfect (inter-class correlation coefficient (ICC) = 0.978, 0.997). There was substantial agreement between both observers for the qualitative assessment of the studied lesions in color ASL images (Kappa = 0.779, with % of agreement = 87.0%). The mean aTBF for grade I tumors was (24.64 ± 3.45 ml/100 g/min), for grade II tumors it was (33.81 ± 3.59 ml/100 g/min), while for high-grade tumors (grade III and IV tumors) it was (75.60 ± 20.0 ml/100 g/min) with (p < 0.001). The mean rTBF of grade I, II, and III/IV tumors was (1.01 ± 0.17); (1.07 ± 0.31); and (3.12 ± 0.24) with (p < 0.001).ConclusionsArterial spin-labeled perfusion MRI can help in the challenge of prediction of brain tumor grading in pediatrics with accurate quantitative and semi-quantitative measurements of perfusion parameters of the tumors as well as qualitative and visual assessment of the tumors.

Diagnosis of Delayed Cerebral Ischemia in Patients with Aneurysmal Subarachnoid Hemorrhage and Triggers for Intervention

IntroductionDelayed cerebral ischemia (DCI) is a major determinant for poor neurological outcome after aneurysmal subarachnoid hemorrhage (aSAH). Detection and treatment of DCI is a key component in the neurocritical care of patients with aSAH after initial aneurysm repair.MethodsNarrative review of the literature.ResultsOver the past 2 decades, there has been a paradigm shift away from macrovascular (angiographic) vasospasm as a main diagnostic and therapeutic target. Instead, the pathophysiology of DCI is hypothesized to derive from several proischemic pathomechanisms. Clinical examination remains the most reliable means for monitoring and treatment of DCI, but its value is limited in comatose patients. In such patients, monitoring of DCI is usually based on numerous neurophysiological and/or radiological diagnostic modalities. Catheter angiography remains the gold standard for the detection of macrovascular spasm. Computed tomography (CT) angiography is increasingly used instead of catheter angiography because it is less invasive and may be combined with CT perfusion imaging. CT perfusion permits semiquantitative cerebral blood flow measurements, including the evaluation of the microcirculation. It may be used for prediction, early detection, and diagnosis of DCI, with yet-to-prove benefit on clinical outcome when used as a screening modality. Transcranial Doppler may be considered as an additional noninvasive screening tool for flow velocities in the middle cerebral artery, with limited accuracy in other cerebral arteries. Continuous electroencephalography enables detection of early signs of ischemia at a reversible stage prior to clinical manifestation. However, its widespread use is still limited because of the required infrastructure and expertise in data interpretation. Near-infrared spectroscopy, a noninvasive and continuous modality for evaluation of cerebral blood flow dynamics, has shown conflicting results and needs further validation. Monitoring techniques beyond neurological examinations may help in the detection of DCI, especially in comatose patients. However, these techniques are limited because of their invasive nature and/or restriction of measurements to focal brain areas.ConclusionThe current literature review underscores the need for incorporating existing modalities and developing new methods to evaluate brain perfusion, brain metabolism, and overall brain function more accurately and more globally.

BI26 Treatment-induced scleroderma in a patient with metastatic melanoma

Abstract We present a 71-year-old woman who presented with sclerodermoid plaques affecting the abdomen and lower limbs, following a single cycle of nivolumab and ipilimumab 20 months prior for BRAF-mutant metastatic melanoma (pulmonary and hepatic metastases). Immunotherapy was discontinued owing to iatrogenic colitis, confirmed on flexible sigmoidoscopy, and requiring oral prednisolone, infliximab and, later, modified-release beclomethasone dipropionate. Owing to the progression of hepatic disease, she was commenced on targeted therapy with dabrafenib and trametinib. A lesional punch biopsy was performed; histological analysis demonstrated a dense dermis with mild chronic inflammatory infiltrate, in keeping with a diagnosis of scleroderma. Treatment with a combination of topical corticosteroids and vitamin D analogues improved disease from 15% body surface area (BSA) to 3% after 4 months. We performed a literature search in PubMed for articles on immunotherapy-related scleroderma published up to August 2022 and identified 18 articles that met our inclusion criteria. Scleroderma was reported in patients with melanoma, non-small-cell lung cancer, renal cell carcinoma, rectal adenocarcinoma, adenocarcinoma of the lung and large-cell neuroendocrine lung cancer treated with pembrolizumab, nivolumab, atezolizumab and ipilimumab. Latency of onset ranged from 0 to 18 months, and treatment included topical and systemic corticosteroids, mycophenolate mofetil, hydroxychloroquine, cyclophosphamide, infliximab and immunoglobulins, with varying treatment outcomes. There was no clear relationship between cancer subtype, duration of treatment and response to treatment. Furthermore, the lack of documented quantitative or semiquantitative measurements for improvement such as BSA and modified Rodnan skin score is limiting. Our case report is important in promoting the awareness of localized scleroderma as a rare side-effect of immunotherapy and highlights the various treatment options available.

Systemic arterial calcium burden in patients with chronic limb-threatening ischemia

Introduction5-year mortality of chronic limb-threatening ischemia (CLTI) is 50–60% and coronary artery disease (CAD) is the main cause of death of CLTI patients, followed by stroke. The aim of this study is to quantify and qualify the calcium load in different arterial territories in patients with CLTI. MethodsProspectively, 60 patients with CLTI were included and received a full-body CT scan. 6 patients were excluded. Different arterial territories (the peripheral lower extremity arteries, coronary arteries, extracranial and intracranial carotid arteries, thoracic and abdominal aorta) were analyzed. Analysis and interrelations of both quantitative and semi-quantitative CT measurements was performed. ResultsMean age was 72 years (range 47–95; SD 11.4). Almost all CLTI patients had calcified arterial beds (femoropopliteal 100%, crural 98.1%, coronary 100%, carotid bifurcation 96.2%, internal carotid artery 98.1%, thoracic aorta 96.2%, abdominal aorta 92.3%). Nearly all arterial territories had severe calcifications. 57% had a very high coronary Agatston score (>1000), and 35% extremely high (>2000). Calcifications in the lower extremity were significantly correlated to CAC score, carotid artery bifurcation calcification score, and to a lesser extent correlated to annular calcifications in the aorta. Very high and extremely high total CAC scores were strongly correlated with severe lower extremity arterial calcifications and severe carotid and intracranial internal carotid artery, thoracic and abdominal aorta calcifications in patients with CLTI patients. ConclusionsIn CLTI patients nearly all arterial territories are severely calcified, suggesting that systemic calcification plays an important role in the poor outcome of this disease.

Evidence for solanidine as a dietary CYP2D6 biomarker: Significant correlation with risperidone metabolism.

The extensive variability in cytochrome P450 2D6 (CYP2D6) metabolism is mainly caused by genetic polymorphisms. However, there is large, unexplained variability in CYP2D6 metabolism within CYP2D6 genotype subgroups. Solanidine, a dietary compound found in potatoes, is a promising phenotype biomarker predicting individual CYP2D6 metabolism. The aim of this study was to investigate the correlation between solanidine metabolism and the CYP2D6-mediated metabolism of risperidone in patients with known CYP2D6 genotypes. The study included therapeutic drug monitoring (TDM) data from CYP2D6-genotyped patients treated with risperidone. Risperidone and 9-hydroxyrisperidone levels were determined during TDM, and reprocessing of the respective TDM full-scan high-resolution mass spectrometry files was applied for semi-quantitative measurements of solanidine and five metabolites (M402, M414, M416, M440 and M444). Spearman's tests determined the correlations between solanidine metabolic ratios (MRs) and the 9-hydroxyrisperidone-to-risperidone ratio. A total of 229 patients were included. Highly significant, positive correlationswere observed between all solanidine MRs and the 9-hydroxyrisperidone-to-risperidone ratio (ρ>0.6, P < .0001). The strongest correlation was observed for the M444-to-solanidine MR in patients with functional CYP2D6 metabolism, i.e., genotype activity scores of 1 and 1.5 (ρ 0.72-0.77, P< .0001). The present study shows strong, positive correlations between solanidine metabolism and CYP2D6-mediated risperidone metabolism. The strong correlation within patients carrying CYP2D6 genotypes encoding functional CYP2D6 metabolism suggests that solanidine metabolism may predict individual CYP2D6 metabolism, and hence potentially improve personalized dosing of drugs metabolized by CYP2D6.

434 Ionizing radiation acoustic imaging (iRAI) for volumetric mapping the dose deep in the liver during radiation therapy

OBJECTIVES/GOALS: The goal of this study was to develop a clinically applicable technique to increase the precision of in vivo dose monitoring during radiation therapy by mapping the dose deposition and resolving the temporal dose accumulation while the treatment is being delivered in real time. METHODS/STUDY POPULATION: Ironizing radiation acoustic imaging (iRAI) is a novel imaging concept with the potential to map the delivered radiation dose on anatomic structure in real time during external beam radiation therapy without interrupting the clinical workflow. The iRAI system consisted of a custom-designed two-dimensional (2D) matrix transducer array with integrated preamplifier array, driven by a clinic-ready ultrasound imaging platform. The feasibility of iRAI volumetric imaging in mapping dose delivery and real-time monitoring of temporal dose accumulation in a clinical treatment plan were investigated with a phantom, a rabbit model, and a cancer patient. RESULTS/ANTICIPATED RESULTS: The total dose deposition and temporal dose accumulation in 3D space of a clinical C-shape treatment plan in a targeted region were first imaged and optimized in a phantom. Then, semi-quantitative iRAI measurements were achieved in an in vivo rabbit model. Finally, for the first time, real-time visualization of radiation dose delivered deep in a patient with liver metastases was performed with a clinical linear accelerator. These studies demonstrate the potential of iRAI to monitor and quantify the radiation dose deposition during treatment. DISCUSSION/SIGNIFICANCE: Described here is the pioneering role of an iRAI system in mapping the 3D radiation dose deposition of a complex clinical radiotherapy treatment plan. iRAI offers a cost-effective and practical solution for real-time visualization of 3D radiation dose delivery, potentially leading to personalized radiotherapy with optimal efficacy and safety.

Evaluation and comparison of four quantitative SARS-CoV-2 serological assays in COVID-19 patients and immunized healthy individuals, cancer patients, and patients with immunosuppressive therapy

BackgroundSemi-quantitative and quantitative immunoassays are the most commonly used methodology to evaluate immunity post immunization. Objectives: To compare four quantitative SARS-CoV-2 serological assays in COVID-19 patients and immunized healthy individuals, cancer patients, and patients with immunosuppressive therapy. Study design: 210 serological samples from COVID-19 infection and vaccination cohorts were used to create a serological sample repository. Serological methods from four manufacturers, namely Euroimmun, Roche, Abbott, and DiaSorin, were evaluated for quantitative, semi-quantitative, and qualitative antibody measurements. All four methods measure IgG antibodies against the SARS-CoV-2 spike receptor–binding domain and report the results in Binding Antibody Unit/mL (BAU/mL). A Total Error Allowable (TEa) of ±25% was chosen as the criteria to determine whether two methods are clinically equivalent quantitatively. Semi-quantitative results (titers) were derived using numeric antibody concentration divided by the cut-off value for each method. Results: All paired quantitative comparisons demonstrated unacceptable performance. With ±25% as TEa, the best agreement was 74 (35.2% out of 210 samples) between Euroimmun and DiaSorin, whereas the lowest agreement was 11 (5.2% out of 210 samples) between Euroimmun and Roche. Antibody titers amongst all four methods were significantly different (p < 0.001). The highest titer difference from the same sample is between Roche and DiaSorin with a 1392-fold difference. On qualitative comparison, none of the paired comparison showed acceptable comparison (p < 0.001). Conclusions: Poor correlation exists between four evaluated assays, quantitatively, semi-quantitatively, and qualitatively. Further harmonization of assays is required to achieve comparable measurements.

Diagnostic efficacy of diffusion-weighted imaging and semiquantitative and quantitative dynamic contrast-enhanced magnetic resonance imaging in salivary gland tumors.

Increased use of functional magnetic resonance imaging (MRI) methods such as diffusion-weighted imaging (DWI) and dynamic contrast-enhanced (DCE) MRI consisting of sequential contrast series, allows us to obtain more information on the microstructure, cellularity, interstitial distance, and vascularity of tumors, which has increased the discrimination power for benign and malignant salivary gland tumors (SGTs). In the last few years, quantitative DCE MRI data containing T1 perfusion parameters (Ktrans, Kep and Ve), were reported to contribute to the differentiation of benign or malignant subtypes in SGTs. To evaluate the diagnostic efficacy of DWI and semiquantitative and quantitative perfusion MRI parameters in SGTs. Diffusion MRI [apparent diffusion coefficient (ADC) value] with a 1.5 T MR machine, semiquantitative perfusion MRI [time intensity curve (TIC) pattern], and quantitative perfusion MRI examinations (Ktrans, Kep and Ve) of 73 tumors in 67 patients with histopathological diagnosis performed from 2017 to 2021 were retrospectively evaluated. In the ADC value and semiquantitative perfusion MRI measurements, cystic components of the tumors were not considered, and the region of interest (ROI) was manually placed through the widest axial section of the tumor. TIC patterns were divided into four groups: Type A = Tpeak > 120 s; type B = Tpeak ≤ 120 s, washout ratio (WR) ≥ 30%; type C = Tpeak ≤ 120 s, WR < 30%; and type D = flat TIC. For the quantitative perfusion MRI analysis, a 3D ROI was placed in the largest solid component of the tumor, and the Ktrans, Kep and Ve values were automatically generated. The majority of SGTs were located in the parotid glands (86.3%). Of all the SGTs, 68.5% were benign and 31.5% were malignant. Significant differences were found for ADC values among pleomorphic adenomas (PMAs), Warthin's tumors (WTs), and malignant tumors (MTs) (P < 0.001). PMAs had type A and WTs had type B TIC pattern while the vast majority of MTs and other benign tumors (OBTs) (54.5% and 45.5%, respectively) displayed type C TIC pattern. PMAs showed no washout, while the highest mean WR was observed in WTs (59% ± 11%). Ktrans values of PMAs, WTs, OBTs, and MTs were not significantly different. Kep values of PMAs and WTs were significantly different from those of OBTs and MTs. Mean Ve value of WTs was significantly different from those of PMAs, OBTs, and MTs (P < 0.001). The use of quantitative DCE parameters along with diffusion MRI and semiquantitative contrast-enhanced MRI in SGTs could improve the diagnostic accuracy.