Asymmetry of thalamic hypometabolism on FDG-PET/CT in neurofibromatosis type 1: Association with peripheral tumor burden.

BACKGROUND AND PURPOSE: Thalamic hypometabolism is a consistent finding in brain PET with F-18 fluorodeoxyglucose (FDG) in patients with neurofibromatosis type 1 (NF1). However, the pathophysiology of this metabolic alteration is unknown. We hypothesized that it might be secondary to disturbance of peripheral input to the thalamus by NF1-characteristic peripheral nerve sheath tumors (PNSTs). To test this hypothesis, we investigated the relationship between thalamic FDG uptake and the number, volume, and localization of PNSTs. METHODS: This retrospective study included 22 adult NF1 patients (41% women, 36.2 ± 13.0 years) referred to whole-body FDG-PET/contrast-enhanced CT for suspected malignant transformation of PNSTs and 22 sex- and age-matched controls. Brain FDG uptake was scaled voxelwise to the individual median uptake in cerebellar gray matter. Bilateral mean and left-right asymmetry of thalamic FDG uptake were determined using a left-right symmetric anatomical thalamus mask. PNSTs were manually segmented in contrast-enhanced CT. RESULTS: Thalamic FDG uptake was reduced in NF1 patients by 2.0 standard deviations (p < .0005) compared to controls. Left-right asymmetry was increased by 1.3 standard deviations (p = .013). Thalamic hypometabolism was higher in NF1 patients with ≥3 PNSTs than in patients with ≤2 PNSTs (2.6 vs. 1.6 standard deviations, p = .032). The impact of the occurrence of paraspinal/paravertebral PNSTs and of the mean PNST volume on thalamic FDG uptake did not reach statistical significance (p = .098 and p = .189). Left-right asymmetry of thalamic FDG uptake was not associated with left-right asymmetry of PNST burden (p = .658). CONCLUSIONS: This study provides first evidence of left-right asymmetry of thalamic hypometabolism in NF1 and that it might be mediated by NF1-associated peripheral tumors.

Accuracy of preoperative CT staging of acute colonic diverticulitis using the classification of diverticular disease (CDD) - Is there a beneficial impact of water enema and visceral obesity?

PURPOSE: We evaluated the accuracy of preoperative CT in staging colonic diverticulitis (ACD) by using the classification of diverticular disease (CDD) and investigated the diagnostic impact of water enema (WE) and visceral obesity. METHODS: In this retrospective study, the radiological and hospital information system was searched for patients who underwent CT for clinically suspected ACD prior to surgery between 2009 and 2019. From the initial population (n = 164), we included 155 patients (94.5 %) (85 women; mean age: 58 ±â€¯13 years) matching the following inclusion criteria: i.) clinically suspected ACD, ii.) i.v. contrast-enhanced CT, iii.) surgery for ACD within 1 week after CT, iv.) histopathological report that proved ACD. The remaining 9 patients (5.5 %) were excluded because histopathological reports were lacking (n = 3) or CT was performed without intravenous contrast agent (n = 6). WE (+ butylscopolamine i.v.) was performed in 93 patients (group A, 60 %). 62 patients (group B, 40 %) had no WE. Visceral-to-subcutaneous fat ratio (V/S) was determined for each patient. Two radiologists blinded for final diagnosis independently staged ACD according to CDD and assessed prevalence and confidence ratings of ACD-related CT-findings: pericolonic fat stranding, covered- and free-perforation, local and generalized peritonitis, abscess. Interobserver-agreement of CT-findings were assessed and effects of WE and V/S ratio on the diagnostic accuracy of CT with surgical and histopathological findings as reference were determined by calculating a logistic regression model. RESULTS: CT-staging showed high accuracy (94 %) and excellent interrater-correlation (ICC 0.96) for staging ACD. WE had no positive impact neither on diagnostic accuracy of staging, nor on confidence ratings of ACD-related CT-findings (all p > 0.5). Confidence ratings were significantly higher in examinations without WE for perforation, peritonitis as well as abscesses (all p < 0.5). Confidence ratings for the assessment of local peritonitis improved significantly with higher V/S (p = 0.049). The increase of V/S significantly correlated with the probability for correct CDD staging of ACD in CT (p = 0.023). CONCLUSION: Increase of visceral obesity significantly improves accuracy of CT in preoperative staging acute colonic diverticulitis. However, independently of the degree of visceral obesity, water enema has no diagnostic benefit and may therefore be omitted. Overall, CT proves high accuracy in preoperative staging ACD using the classification of diverticular disease. LEVEL OF EVIDENCE: Retrospective study, observational study.

Nanobodies effectively modulate the enzymatic activity of CD38 and allow specific imaging of CD38+ tumors in mouse models in vivo.

The cell surface ecto-enzyme CD38 is a promising target antigen for the treatment of hematological malignancies, as illustrated by the recent approval of daratumumab for the treatment of multiple myeloma. Our aim was to evaluate the potential of CD38-specific nanobodies as novel diagnostics for hematological malignancies. We successfully identified 22 CD38-specific nanobody families using phage display technology from immunized llamas. Crossblockade analyses and in-tandem epitope binning revealed that the nanobodies recognize three different non-overlapping epitopes, with four nanobody families binding complementary to daratumumab. Three nanobody families inhibit the enzymatic activity of CD38 in vitro, while two others were found to act as enhancers. In vivo, fluorochrome-conjugated CD38 nanobodies efficiently reach CD38 expressing tumors in a rodent model within 2 hours after intravenous injection, thereby allowing for convenient same day in vivo tumor imaging. These nanobodies represent highly specific tools for modulating the enzymatic activity of CD38 and for diagnostic monitoring CD38-expressing tumors.

Untargeted profiling of tracer-derived metabolites using stable isotopic labeling and fast polarity-switching LC-ESI-HRMS.

An untargeted metabolomics workflow for the detection of metabolites derived from endogenous or exogenous tracer substances is presented. To this end, a recently developed stable isotope-assisted LC-HRMS-based metabolomics workflow for the global annotation of biological samples has been further developed and extended. For untargeted detection of metabolites arising from labeled tracer substances, isotope pattern recognition has been adjusted to account for nonlabeled moieties conjugated to the native and labeled tracer molecules. Furthermore, the workflow has been extended by (i) an optional ion intensity ratio check, (ii) the automated combination of positive and negative ionization mode mass spectra derived from fast polarity switching, and (iii) metabolic feature annotation. These extensions enable the automated, unbiased, and global detection of tracer-derived metabolites in complex biological samples. The workflow is demonstrated with the metabolism of (13)C9-phenylalanine in wheat cell suspension cultures in the presence of the mycotoxin deoxynivalenol (DON). In total, 341 metabolic features (150 in positive and 191 in negative ionization mode) corresponding to 139 metabolites were detected. The benefit of fast polarity switching was evident, with 32 and 58 of these metabolites having exclusively been detected in the positive and negative modes, respectively. Moreover, for 19 of the remaining 49 phenylalanine-derived metabolites, the assignment of ion species and, thus, molecular weight was possible only by the use of complementary features of the two ion polarity modes. Statistical evaluation showed that treatment with DON increased or decreased the abundances of many detected metabolites.

Postmortem 31P magnetic resonance spectroscopy of the skeletal muscle: α-ATP/Pi ratio as a forensic tool?

PURPOSE: Phosphor magnetic resonance spectroscopy ((31)P MRS) is an established method for metabolic examinations of resting and exercising skeletal muscle. So far, there are few MRS investigations of human corpses. The aim of this study was to investigate the temporal postmortem pattern of phosphor metabolites in the adductor magnus muscle and to check the value of MRS as a forensic tool, especially for the determination of the time of death. MATERIAL AND METHODS: Eight corpses, died of natural cause, were examined (5 males, 3 females; age: 73±7 y, weight 65.8±15.9 kg). A control group of 3 subjects (2 males, 1 female, mean age: 51±24 y, range: 24-69 y, mean body weight: 84.0±16.5 kg) was examined at a single time point as well. (31)P MRS was performed on a 1.5 T MRI (TR 700 ms, TE 0.35 ms, averages 256, flip angle 90°). A standard (31)P/(1)H heart/liver coil was employed (receiver coil diameter 12 cm). The (31)P MRS scans were repeated in intervals of 1 h over a period from 4.5 to 24 h postmortem (p.m.). The core temperature was rectally measured throughout the MRI examination. RESULTS: The mean core temperature decreased from 36.0°C to 25.7°C. In vivo and ex vivo spectra showed characteristic differences, especially the PCr metabolite was no longer detectable after 10 h p.m. The α-ATP/Pi ratio decreased with time from 0.445 to 0.032 over 24 h p.m. CONCLUSION: There is a characteristic postmortem time pattern of the phosphor metabolites. Especially the acquired α-ATP/Pi ratio could be described by a significant exponential time course (r(2)=0.92, p<0.001). (31)P MRS might be added to the postmortem imaging methods.

Isolation and characterization of a new less-toxic derivative of the Fusarium mycotoxin diacetoxyscirpenol after thermal treatment.

Trichothecenes are an important class of mycotoxins that act as potent protein synthesis inhibitors in eukaryotic organisms. The compound 4,15-diacetoxyscirpenol is highly toxic for plants and animals. Potatoes are especially prone to be contaminated with 4,15-diacetoxyscirpenol after infection with Fusarium sambucinum. In the current study, the reduction of 4,15-diacetoxyscirpenol during thermal treatment in aqueous solution was monitored. A new derivative was detected and named DAS-M1. After isolation, DAS-M1 was characterized with LC-HR-MS and LC-MS/MS and structurally elucidated with (1)H, (13)C, and 2D NMR. Potatoes were inoculated with F. sambucinum, and the infected potatoes were cooked at 100 or 121 °C, respectively. A reduction of 4,15-diacetoxyscirpenol from about 26% (1 h at 100 °C) to 100% (4 h at 121 °C) was detected by means of LC-MS/MS analysis. The effects of different pH values on the reduction of 4,15-diacetoxyscirpenol were investigated, showing higher conversion rates at more acidic pH values. In addition, the toxicity of 4,15-diacetoxyscirpenol and DAS-M1 was compared in vitro using a wheat germ transcription/translation assay and in vivo on Saccharomyces cerevisiae. The results show that the inhibitory effect of DAS-M1 on yeast growth is about 50 times lower and inhibition of protein synthesis is about 100 times lower than that of 4,15-diacetoxyscirpenol.