Comparative Study of Initial Post-Therapeutic 131I Single-Photon Emission Computed Tomography/Computed Tomography and Reoperation for the Detection of Residual Lymph Node Metastasis in Patients With Papillary Thyroid Cancer

ObjectiveTo assess the diagnostic performance of initial post-therapeutic ¹³¹I single-photon emission computed tomography/computed tomography (SPECT/CT) compared with that of reoperation in detecting residual lymph node metastasis (LNM).MethodsPatients with iodine-avid LNM detected on the initial post-therapeutic ¹³¹I SPECT/CT and who underwent reoperative dissection within 6 months were included. LNMs (numbers and locations) detected via both methods were compared. The American Thyroid Association dynamic risk stratification was performed for patients receiving second radioactive iodine therapy after reoperation.ResultsFifty-three patients with 95 iodine-avid LNMs detected by ¹³¹I SPECT/CT were enrolled. Fifty-one (96.2%) patients had 212 LNMs confirmed by reoperation (P = .004). The sensitivity and specificity of ¹³¹I SPECT/CT in detecting LNM were 44.8% (95/212) and 91.6% (87/95), respectively. The location frequency of residual LNMs found by ¹³¹I SPECT/CT was similar to that of reoperation (P = .057). Thirty-two patients received a second radioactive iodine treatment, and 6 (18.8%) patients still had residual iodine-avid LNM on SPECT/CT. Therapeutic response was evaluated by American Thyroid Association dynamic risk stratification in 16 patients. The number of patients with structural incomplete response, biochemical incomplete response, indeterminate response, and excellent response was 4 (23.5%), 4 (23.5%), 5 (29.4%), and 3 (17.6%), respectively.Conclusion¹³¹I SPECT/CT has high specificity but relatively low sensitivity in detecting all residual LNMs. Approximately 80% of patients were rendered structurally disease free after reoperation.     

Cystic Parathyroid Adenomas: An Enigmatic Entity and Role of Tc-99 m Sestamibi Scintigraphy

ObjectiveFunctional cystic lesion of the parathyroid gland is a rare cause of primary hyperparathyroidism (PHPT). They have been postulated to arise from the hemorrhage and cystic degeneration in the parathyroid adenoma (PA). We intended to analyze their scintigraphic and histopathological findings since available literature is sparse.MethodsDual-phase ^{99 m}Tc-sestamibi planar and SPECT/CT scans performed from January 2014 to January 2020 in patients presenting with PHPT were retrospectively analyzed. The clinical, biochemical, and ultrasound features were collected. Planar and SPECT/CT imaging parameters were analyzed. Detailed histopathological analysis, along with post-surgical clinical and biochemical features of the patients who underwent surgery, was reviewed with a mean follow-up of 21.8 ± 20.1 months.ResultsOf the 979 scans analyzed, 10 showed cystic parathyroid lesions (M:F- 3:7, mean age 45.6 ± 15 years, range: 23-66). The predominant presenting features in patients were abdominal pain and renal stone disease, present in 60% of the patients. On planar scintigraphy, 90% of the patients had tracer avid distinct lesions, whereas tracer activity was seen in the solid part of the cystic lesions in all 10 patients on SPECT/CT, with cystic areas showing an attenuation of 23.1 ± 7.6 HU. Eight of these patients underwent surgery, with all showing PA with cystic changes on histopathology. Two of these patients also showed hemorrhage within the cystic spaces.ConclusionHemorrhage within a PA may give rise to cystic parathyroid lesions with PHPT. ^{99 m}Tc-sestamibi scintigraphy with dual-phase imaging and SPECT/CT may help in detecting this rare entity.     

Comparison of 90Y SIRT predicted and delivered absorbed doses using a PSF conversion method

PurposeThe aims of this study were to develop and apply a method to correct for the differences in partial volume effects of pre-therapy Technetium-99 m (^99mTc)-MAA SPECT and post-therapy Yttrium-90 (⁹⁰Y) bremsstrahlung SPECT imaging in selective internal radiation therapy, and to use this method to improve quantitative comparison of predicted and delivered ⁹⁰Y absorbed doses.MethodsThe spatial resolution of ^99mTc SPECT data was converted to that of ⁹⁰Y SPECT data using a function calculated from ^99mTc and ⁹⁰Y point spread functions. This resolution conversion method (RCM) was first applied to ^99mTc and ⁹⁰Y SPECT phantom data to validate the method, and then to clinical data to assess the power of ^99mTc SPECT imaging to predict the therapeutic absorbed dose.ResultsThe maximum difference between absorbed doses to phantom spheres was 178%. This was reduced to 27% after the RCM was applied.The clinical data demonstrated differences within 38% for mean absorbed doses delivered to the normal liver, which were reduced to 20% after application of the RCM. Analysis of clinical data showed that therapeutic absorbed doses delivered to tumours greater than 100 cm³ were predicted to within 52%, although there were differences of up to 210% for smaller tumours, even after the RCM was applied.ConclusionsThe RCM was successfully verified using phantom data. Analysis of the clinical data established that the ^99mTc pre-therapy imaging was predictive of the ⁹⁰Y absorbed dose to the normal liver to within 20%, but had poor predictability for tumours smaller than 100 cm³.     

Parathyroid Cystic Adenoma: A Systematic Review and Meta-Analysis

ObjectiveTo review diagnostic imaging modalities for parathyroid cystic adenomas (PCA). Since PCAs are a rare (0.5%-1%) subclass of parathyroid adenomas, and due to their cystic component, imaging modalities known to be efficient for diagnosing solid adenomas might fail in localizing them.MethodsWe conducted a systematic review using the PubMed and Cochrane databases for English articles on PCAs published between 1995 and 2020. A meta-analysis of the retrieved data was performed.ResultsOverall, 39 studies, reporting on a total of 160 patients, were included in the analysis. Two thirds (68%) of the patients were female, with a mean age of 53.9 years. A single cystic adenoma was detected in 98.1% of cases. The mean blood calcium corrected for albumin level was 12.6 ± 2.7 mg/dL, and the mean parathyroid hormone level was 565.5 ± 523.8 pg/mL. The mean PCA sizes as measured by ultrasound (US), computed tomography (CT), and ex vivo measurement were 4.8 ± 3.6, 5.2 ± 3.2, and 3.5 cm, respectively. The median weight was 8.1 g. PCA was detected in 86% of US examinations; 100% of US-guided fine needle aspiration, 4-dimensional computed tomography (4D-CT), or magnetic resonance imaging examinations; and 61% of 99m-technetium sestamibi scan with single-photon emission computed tomography ((99m)Tc-SPECT). (99m)Tc-SPECT showed a significantly lower diagnostic rate than US (odds ratio, 3.589), US-guided fine needle aspiration, CT combined with 4D-CT, and the combination of US, CT, 4D-CT, and magnetic resonance imaging (P < .001).ConclusionAlthough US and 4D-CT showed a significantly high rate in diagnosing PCA, (99m)Tc-SPECT showed a lower PCA diagnostic rate. These findings suggest that larger cystic lesions suspected as PCAs should be further evaluated using 4D-CT rather than (99m)Tc-SPECT.     

18F-FDG Micro PET/CT imaging to evaluate the effect of BRCA1 knockdown on MDA-MB231 breast cancer cell radiosensitivity

ObjectiveRadioresistance of tumor cells is a major factor associated with failure of radiotherapy (RT). This study aimed to investigate the effect of BRCA1 knockdown on MDA-MB231 breast cancer cell radiosensitivity.Materials and methodsShort hairpin RNA (shRNA) was used to knockdown BRCA1 gene in MDA-MB231 cells. Cell viability and proliferative capacity were assessed by CCK-8 and colony formation assays, respectively. We established xenograft models in nude mice to evaluate tumor volume and tumor weight. The mice were imaged by ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT) before and after RT to evaluate changes in maximum standardized uptake value (SUV_max) and tumor SUV_max/muscle SUV_max (TMR). Changes in HIF-1α, Glut-1 and Ki-67 were analyzed and the correlation between ¹⁸F-FDG uptake and tumor biology was analyzed.ResultsCompared with the control cells, RT significantly reduced cell viability and colony formation capacity in cells with the BRCA1 gene knockdown. In vivo assays showed that there was obvious delay in the tumor growth in the shBRCA1+RT group compared with the control group. ¹⁸F-FDG Micro PET/CT indicated a reduction in glucose metabolism in the shBRCA1+RT group, with statistically significant differences in both the SUV_max and TMR. The data showed the expression of HIF-1α, Glut-1 and Ki-67 was downregulated in the shBRCA1+RT group, and both SUVmax and TMR had significant correlation with tumor biology.ConclusionThese results demonstrated that BRCA1 knockdown improves the sensitivity of MDA-MB231 breast cancer cells to RT. In addition, ¹⁸F-FDG PET/CT imaging allows non-invasive analysis of tumor biology and assessment of radiosensitivity.     

The Role of Surgeon-Performed Office and Preincision Ultrasounds in Localization of Parathyroid Adenomas in Primary Hyperparathyroidism

ObjectiveWe studied the use of surgeon-performed office ultrasound (OU) and preincision ultrasound (PIU) in preoperatively localizing parathyroid adenomas in primary hyperparathyroidism (PHPT).MethodsA retrospective chart review was performed for patients with PHPT who underwent parathyroidectomy between 2013 and 2015. The results of OU and PIU were recorded and compared with the final surgical pathology.ResultsOf 348 patients with PHPT, 285 (81.9%) had single-lesion disease, 49 (14.1%) had double-lesion disease, and 14 (4.0%) had multigland disease with 3 or more lesions. For single-lesion disease, the overall sensitivity and specificity of OU to correctly lateralize the lesion were 64.2% and 91.2%, while those of PIU were 89.4% and 93.6%, respectively. The sensitivity and specificity of PIU were comparable to those of 4-dimensional computed tomography (87.1% and 90.7%, respectively) and ^99mTc-sestamibi scintigraphy (70.4% and 95.9%, respectively). While the majority of PIU cases were preceded by other imaging studies, the accuracy in localizing lesions was not largely affected by the presence of prior computed tomography and/or ^99mTc-sestamibi scintigraphy, as opposed to ultrasounds only. For detecting the presence of multigland disease, the sensitivity and specificity of OU were 26% and 92.2%, while those of PIU were 64.3% and 94.7%, respectively.ConclusionSurgeon-performed OU and PIU are valuable tools in preoperatively localizing the parathyroid adenoma in single-lesion disease, while their utility may be limited for double-lesion or multigland disease. PIU in particular yields high accuracy in detecting parathyroid lesions in combination with other imaging modalities.     

Overview of commercial treatment planning systems for targeted radionuclide therapy

IntroductionTargeted Radionuclide Therapy (TRT) is a branch of cancer medicine dealing with the therapeutic use of radioisotopes associated with biological vectors accumulating in the tumors/targets, indicated as Molecular Radiotherapy (MRT), or directly injected into the arteries that supply blood to liver tumour vasculature, indicated as Selective RT (SRT). The aim of this work is to offer a panoramic view on the increasing number of commercially-available TRT treatment planning systems (TPSs).Materials and methodsA questionnaire was sent to manufacturers' representatives. Academic software were not considered. Questions were grouped as follows: general information, clinical workflow, calibration procedure, image processing/reconstruction, image registration and segmentation tools, time-activity curve (TAC) fitting and absorbed dose calculation.ResultsAll software reported have CE-marking. TPSs were divided between SRT-dedicated software [4] and MRT [5] dosimetry software. In SRT, since no kinetic process is involved, absorbed dose calculation does not require TAC fitting, and image registration is not fully developed in all TPS. All software requires a radionuclide-specific calibration. In SRT, a relative image calibration can be obtained by scaling the counts to a known activity. Automated VOI contouring and rigid/deformable propagation between different acquisitions time-points is implemented in most TPSs, although DICOM export is rare. Different TAC fits are available depending on the number of time-points. Voxel S-value and Local deposition methods are the most frequent dosimetric approaches; dose-voxel kernel convolution and semi-Monte Carlo method are also available.ConclusionsAvailable TPSs allows performing personalized dosimetry in clinical practice. Individual variations in methodology/algorithms must be considered in the standardisation/harmonization processes.     

Validation of low-dose lung cancer PET-CT protocol and PET image improvement using machine learning

PurposeTo conduct a simplified lesion-detection task of a low-dose (LD) PET-CT protocol for frequent lung screening using 30% of the effective PETCT dose and to investigate the feasibility of increasing clinical value of low-statistics scans using machine learning.MethodsWe acquired 33 SD PET images, of which 13 had actual LD (ALD) PET, and simulated LD (SLD) PET images at seven different count levels from the SD PET scans. We employed image quality transfer (IQT), a machine learning algorithm that performs patch-regression to map parameters from low-quality to high-quality images. At each count level, patches extracted from 23 pairs of SD/SLD PET images were used to train three IQT models – global linear, single tree, and random forest regressions with cubic patch sizes of 3 and 5 voxels. The models were then used to estimate SD images from LD images at each count level for 10 unseen subjects. Lesion-detection task was carried out on matched lesion-present and lesion-absent images.ResultsLD PET-CT protocol yielded lesion detectability with sensitivity of 0.98 and specificity of 1. Random forest algorithm with cubic patch size of 5 allowed further 11.7% reduction in the effective PETCT dose without compromising lesion detectability, but underestimated SUV by 30%.ConclusionLD PET-CT protocol was validated for lesion detection using ALD PET scans. Substantial image quality improvement or additional dose reduction while preserving clinical values can be achieved using machine learning methods though SUV quantification may be biased and adjustment of our research protocol is required for clinical use.     

Dual-energy CT imaging of orbits during episcleral brachytherapy with Ru-106 plaques: A phantom study on its potential for plaque position verification

PurposeTo investigate the potential of dual energy CT (DECT) to suppress metal artifacts and accurately depict episcleral brachytherapy Ru-106 plaques after surgical placement.MethodsAn anthropomorphic phantom simulating the adult head after surgical placement of a Ru-106 plaque was employed. Nine DECT acquisition protocols for orbital imaging were applied. Monochromatic 140 keV images were generated using iterative reconstruction and an available metal artifact reduction algorithm. Generated image datasets were graded by four observers regarding the ability to accurate demarcate the Ru-106 plaque. Objective image quality and visual grading analysis (VGA) was performed to compare different acquisition protocols. The DECT imaging protocol which allowed accurate plaque demarcation at minimum exposure was identified. The eye-lens dose from orbital DECT, with and without the use of radioprotective bismuth eye-shields, was determined using Monte Carlo methods.ResultsAll DECT acquisition protocols were judged to allow clear demarcation of the plaque borders despite some moderate streaking/shading artifacts. The differences between mean observers’ VGA scores for the 9 DECT imaging protocols were not statistically significant (p > 0.05). The eye-lens dose from the proposed low-exposure DECT protocol was found to be 20.1 and 22.8 mGy for the treated and the healthy eye, respectively. Bismuth shielding was found to accomplish >40% reduction in eye-lens dose without inducing shielding-related artifacts that obscure plaque delineation.ConclusionsDECT imaging of orbits after Ru-106 plaque positioning for ocular brachytherapy was found to allow artifact-free delineation of plaque margins at relatively low patient exposure, providing the potential for post-surgery plaque position verification.     

Clinical application of a gantry-attachable plastic scintillating plate dosimetry system in pencil beam scanning proton therapy beam monitoring

PurposeThe entrance beam fluence of therapeutic proton scanning beams can be monitored using a gantry-attachable plastic scintillating plate (GAPSP). This study evaluated the clinical application of the GAPSP using a method that measures intensity modulated proton therapy (IMPT) beams for patient treatment.MethodsIMPT beams for the treatment of nine patients, at sites that included the spine, head and neck, pelvis, and lung, were measured using the GAPSP, composed of an EJ-212 plastic scintillator and a CMOS camera. All energy layers distinguished by the GAPSP were accumulated to determine the dose distribution of the treatment field. The evaluated fields were compared with reference dose maps verified by quality assurance.ResultsComparison of dose distributions of evaluation treatment fields with reference dose distributions showed that the 3%/1 mm average gamma passing rate was 96.4%, independent of the treatment site, energy range and field size. When dose distributions were evaluated using the same criteria for each energy layer, the average gamma passing rate was 91.7%.ConclusionsThe GAPSP is a suitable, low-cost method for monitoring pencil beam scanning proton therapy, especially for non-spot scanning or additional collimation. The GAPSP can also estimate the treatment beam by the energy layer, a feature not common to other proton dosimetry tools.     

The Added Value of Second-Look Ultrasound in Patients With Primary Hyperparathyroidism With Discordant or Negative Previous Imaging Findings

ObjectiveThe preoperative localization for patients with primary hyperparathyroidism with negative or discordant previous imaging results has always been a difficult problem to be solved in clinical practice. Second-look ultrasound (US) is a viable but underestimated method. This study aimed to assess the added value of second-look US and explore the attributing factors.MethodsAmong 711 surgically confirmed patients with primary hyperparathyroidism, 63 patients with negative or discordant first-time US and ^99mTc-MIBI imaging results were retrospectively studied. All 63 patients underwent second-look US, and the results were compared with intraoperative findings and histopathologic diagnosis. The diagnostic value of second-look US was calculated, and the reasons for changed second-look US results were analyzed.ResultsSixty-three parathyroid lesions were found in 63 patients. The sensitivity, positive predictive value, and accuracy of second-look US were 92.1%, 95.1%, and 88.1%, respectively. Comparing the results of first-time and second-look US, we found that 54.0% of the patients got benefits from second-look US because 34 patients with negative results in the first-time US revealed localization with second-look US. Second-look US was more likely to produce changes in results for lesions with a lower location (OR, 3.23; 95% CI, 1.11-9.43, P < .05) and larger length-to-thickness ratio (3.0 vs 2.4, P < .05).ConclusionSecond-look US is a promising method to determine preoperative localization in patients with negative or discordant results of previous imaging findings. Lesions with elongated shape and lower location are more expected to be detected in second-look US when missed at the first time.     

Optimization of image quality and accuracy of low iodine concentration quantification as function of kVp pairs for abdominal imaging using dual-source CT: A phantom study

PurposeTo determine the suitable kVp pair for optimal image quality of the virtual monochromatic images (VMIs) and iodine quantification accuracy at low concentration, using a third generation dual-source CT (DSCT).Materials and methodsMulti-energy CT phantoms with and without body rings were scanned with a DSCT using four kVp pairs (tube “A”/“B” voltage): 100/Sn150, 90/Sn150, 80/Sn150 and 70/Sn150 kVp. The reference mAs was adjusted to obtain a CTDI_vol close to 11 mGy. HU values accuracy (RMSD_HU), noise (SD) and contrast-to-noise ratio (CNR) of iodine inserts of 0.5, 1, 2 and 5 mg/mL concentrations were assessed on VMIs at 40/50/60/70 keV. Iodine quantification accuracy was assessed using the RMSD_iodine and iodine bias (IB_iodine).ResultsThe RMSD_HU decreased when the tube “A” voltage increased. The mean noise value increased significantly with tube “A” voltage (p < 0.001) but decreased between 80/Sn150 and 90/Sn150 kVp for the small phantom (1.1 ± 0.1%; p = 0.047). The CNR significantly decreased with tube “A” voltage (p < 0.001), except between 80/Sn150 and 90/Sn150 kVp for all inserts and between 90/Sn150 kVp and 100/Sn150 kVp for the 1.0 and 0.5 mg/mL inserts in the large phantom. In the small phantom, no significant difference was found between 80/Sn150 kVp and 90/Sn150 kVp for all inserts and between 80/Sn150, 90/Sn150 and 100/Sn150 kVp for the 1 and 0.5 mg/mL inserts. The RMSD_iodine and IB_iodine decreased as the tube “A” voltage of the kVp pair increased.ConclusionThe kVp pair of 70/Sn150 led to better image quality in VMIs and sufficient iodine accuracy.     

Impact of iterative reconstructions on image quality and detectability of focal liver lesions in low-energy monochromatic images

PurposeTo assess the impact of iterative reconstructions on image quality and detectability of focal liver lesions in low-energy monochromatic images from a Fast kV-Switching Dual Energy CT (KVSCT) platform.MethodsAcquisitions on an image-quality phantom were performed using a KVSCT for three dose levels (CTDI_vol:12.72/10.76/8.79 mGy). Raw data were reconstructed for five energy levels (40/50/60/70/80 keV) using Filtered Back Projection (FBP) and four levels of ASIR (ASIR30/ASIR50/ASIR70/ASIR100). Noise power spectrum (NPS) and task-based transfer function (TTF) were measured before computing a Detectability index (d′) to model the detection task of liver metastasis (LM) and hepatocellular carcinoma (HCC) as function of keV.ResultsFrom 40 to 70 keV, noise-magnitude was reduced on average by −68% ± 1% with FBP; −61% ± 3% with ASIR50 and −52% ± 6% with ASIR100. The mean spatial frequency of the NPS decreased when the energy level decreased and the iterative level increased. TTF values at 50% decreased as the energy level increased and as the percentage of ASIR increased. The detectability of both lesions increased with increasing dose level and percentage of ASIR. For the LM, d′ peaked at 70 keV for all reconstruction types, except for ASIR70 at 12.72 mGy and ASIR100, where d' peaked at 50 keV. For HCC, d’ peaked at 60 keV for FBP and ASIR30 but peaked at 50 keV for ASIR50, ASIR70 and ASIR100.ConclusionsUsing percentage of ASIR above 50% at low-energy monochromatic images could limit the increase of noise-magnitude, benefit from spatial resolution improvement and hence enhance detectability of subtle low contrast focal liver lesions such as HCC.     

A scaffold replacement approach towards new sirtuin 2 inhibitors

Sirtuins (SIRT1–SIRT7) are an evolutionary conserved family of NAD⁺-dependent protein deacylases regulating the acylation state of ε-N-lysine residues of proteins thereby controlling key biological processes. Numerous studies have found association of the aberrant enzymatic activity of SIRTs with various diseases like diabetes, cancer and neurodegenerative disorders. Previously, we have shown that substituted 2-alkyl-chroman-4-one/chromone derivatives can serve as selective inhibitors of SIRT2 possessing an antiproliferative effect in two human cancer cell lines. In this study, we have explored the bioisosteric replacement of the chroman-4-one/chromone core structure with different less lipophilic bicyclic scaffolds to overcome problems associated to poor physiochemical properties due to a highly lipophilic substitution pattern required for achieve a good inhibitory effect. Various new derivatives based on the quinolin-4(1H)-one scaffold, bicyclic secondary sulfonamides or saccharins were synthesized and evaluated for their SIRT inhibitory effect. Among the evaluated scaffolds, the benzothiadiazine-1,1-dioxide-based compounds showed the highest SIRT2 inhibitory activity. Molecular modeling studies gave insight into the binding mode of the new scaffold-replacement analogues.     

Poloxamer-chitosan-based Naringenin nanoformulation used in brain targeting for the treatment of cerebral ischemia

ObjectiveHere, the aim is to improve the bioavailability of Naringenin (NRG) in brain and to establish the highest remedial benefit from a novel anti-ischemic medicine i.e. NRG.MethodsA novel Naringenin-loaded-nanoemulsion (NE)-(in situ)-gel (i.e. thermoresponsive), was formulated with the help of Poloxamer-407 (20.0% w/v). Chitosan (CS, 0.50% w/v) was used to introduce the mucoadhesive property of NE-(in situ)-gel and finally called as NRG-NE-gel + 0.50%CS. A novel UHPLC-ESI-Q-TOF-MS/MS-method was optimized and used for NRG-NE-gel + 0.50%CS to quantify the Pharmacokinetic-(PK)-parameters in plasma as well as brain and to evaluate the cerebral ischemic parameters after MCAO i.e. locomotor activity, grip strength, antioxidant activity, and quantity the infarction volume in neurons with the safety/toxicity of NRG-NE-gel + 0.50%CS after i.n. administration in the rats.ResultsThe mucoadhesive potency and gelling temperature of NRG-NE-gel + 0.50%CS were observed 6245.38 dynes/cm² and 28.3 ± 1.0 °C, respectively. Poloxamer-407 based free micelles size was observed 98.31 ± 1.17 nm with PDI (0.386 ± 0.021). The pH and viscosity of NRG-NE-gel + 0.50%CS were found to be 6.0 ± 0.20 and 2447 ± 24cp (at 35.0 ± 1.0 °C temperature), respectively. An elution time and m/z NRG were observed 1.78 min and 270.97/150.96 with 1.22 min and m/z of 301.01/150.98 for Quercetin (IS) respectively. Inter and intra %precision and %accuracy was validated 1.01–3.37% and 95.10–99.30% with a linear dynamic range (1.00 to 2000.00 ng/ml). AUC_0-24 of plasma & brain were observed 995.60 ± 24.59 and 5600.99 ± 144.92 (ng min/ml g) in the rats after the intranasal (i.n.) administration of NRG-NE-gel + 0.50%CS. No toxicological response were not found in terms of mortalities, any-change morphologically i.e. in the microstructure of brain as well as nasal mucosa tissues, and also not found any visual signs in terms of inflammatory or necrosis.ConclusionIntranasally administered NRG-NE-gel + 0.50%CS enhanced the bioavailability of Naringenin in the brain. In the cerebral ischemic rats, significantly improved the neurobehavioral activity (locomotor & grip strength) followed by antioxidant activity as well as infarction volume. Finally, the toxicity studies carried out and established the safe nature of optimized-NRG-NE-gel + 0.50%CS.     

Proteomic analysis of hypoxia and non-hypoxia secretome mesenchymal stem-like cells from human breastmilk

IntroductionBreastmilk contains proteins and cells which have stem cell properties. The human breastmilk stem cell mimick mesenchymal stem cells and expresses pluripotency genes. The protein level of breastmilk is high in colostrum and gradually subsides in the first year of lactation. The mesenchymal stem cells from breastmilk can be an alternative source of stem cells that can potentially affect cardiovascular therapy. This study aimed to identify the proteomic analysis of secretome mesenchymal stem-like cells under hypoxia compared to non-hypoxia from human breastmilk stem cells.Material and methodsThe human breastmilk was collected from six healthy breastfeeding women and transported to the laboratory under aseptic conditions. The breastmilk cells were isolated then cultured. After 72 h, the human breastmilk stem cells reached confluence then cleaned up and isolated in serum-free media (spheroid) to allow serial passaging every 48 h. The acquisition stem cell was made with flow cytometry. The cells were divided into hBSC secretomes under hypoxia (A) and non-hypoxia (B) and analyzed for LC-MS to identify the peptide structure.ResultsThe human breastmilk cells contained several mesenchymal stem-like cells in density 2.4 × 10⁶ cell/mL for hypoxia and 2 × 10⁶ cell/mL for non-hypoxia conditions. The human breastmilk stem cell surface markers derived from the third cell passage process were 93.77% for CD44, 98.69% for CD73, 88.45% for CD90, and 96.30% for CD105. The protein level of secretome mesenchymal stem -like cells under hypoxia was measured at 5.56 μg/mL and 4.28 μg/mL for non-hypoxia. The liquid chromatography-mass spectrometry analysis identified 130 and 59 peptides from hypoxia and non-hypoxia of the human breastmilk stem cell secretome sequentially. Some important proteomics structures were found in the hypoxic human breastmilk stem cell secretome, such as transforming growth factor-β, VE-cadherin, and caspase.ConclusionThe human breastmilk cells contain mesenchymal stem-like cells and a high concentration of CD44, CD73, CD90, and CD105 as surface markers at third passage culture. The hypoxic hBSC secretome produces a higher protein level compare to non-hypoxia. The transforming growth factor -β was found in the hypoxic hBSC secretome as a modulator of VEGF-mediated angiogenesis.     

Etiology-, Sex-, and Tumor Size-Based Differences in Adrenocorticotropin-Dependent Cushing Syndrome

ObjectiveTo examine demographic, clinical, and biochemical differences in patients with adrenocorticotropin (ACTH)-dependent Cushing syndrome (CS) based on etiology, sex, and tumor size.MethodsThis was a single-center study of 211 patients with ACTH-dependent CS followed for 35 years. Patients were stratified into 3 groups based on etiology: Cushing disease (CD)/transsphenoidal surgery, Cushing disease/total bilateral adrenalectomy (CD/TBA), and ectopic ACTH secretion (EAS). Patients were also stratified based on sex and tumor size (nonvisualized, microadenoma, and macroadenoma).ResultsCD was the commonest cause of ACTH-dependent CS (190; 90%). Most patients presented in the third decade (median age, 29 years). Clinical features, cortisol, and ACTH were significantly greater in the EAS group. The CD/TBA group had more nonvisualized tumors (22% vs 8%; P = .000) and smaller tumor size (4 vs 6 mm; P = .001) compared with the CD/transsphenoidal surgery group. There was female predominance in CD (2.06:1) and male predominance in EAS (2:1). Men had shorter duration of symptoms (2 years; P = .014), were younger (23 years; P = .001), had lower body mass index (25.1 kg/m²; P = .000), and had more severe disease (low bone mineral density, hypokalemia). Macroadenomas were frequent (46; 24.2%), and ACTH correlated with tumor size in CD (r = 0.226; P = .005).ConclusionOur cohort presented at an earlier age than the Western population with a distinct, but slightly lower, female predilection. Patients with CD undergoing TBA had frequent negative imaging. Men had a clinical profile suggesting aggressive disease. Microadenoma and macroadenoma were difficult to distinguish on a clinicobiochemical basis.     

Predictive Value of Calcium Test for Preoperative Diagnosis of Medullary Thyroid Carcinoma in Patients With Moderately Elevated Basal Calcitonin

ObjectiveMedullary thyroid carcinoma (MTC) can be very aggressive, and early diagnosis is based on routine measurement of serum calcitonin (CT) and RET genetic testing for hereditary forms. Basal serum CT (bCT) concentrations are useful in the early detection of MTC, although it is still unclear whether they can also be used for the differential diagnosis between MTC and C-cell hyperplasia (CCH). Since false-positive results can be obtained with the basal measurement of CT, a provocative test to evaluate stimulated CT (sCT) is often needed. The objective of this study was to investigate the utility of a calcium gluconate test for CT in distinguishing MTC from CCH, a precancerous condition in hereditary forms of MTCs but with unclear significance in sporadic MTCs.MethodsA total of 74 patients underwent the calcium loading test before thyroidectomy, and bCT and sCT levels were compared with histologic results by receiver operating characteristic plot analyses.ResultsA peak CT level of 388.4 pg/mL after stimulation with calcium gluconate was able to significantly distinguish patients with MTC from those with CCH and those without C-cell pathology, with 81.8% sensitivity and 36.5% specificity. A bCT level of 16.1 pg/mL was able to distinguish between these 2 groups of patients with a sensitivity of 90%.ConclusionHigh-dose calcium test is an effective procedure that can be applied for differential diagnosis of MTC and CCH. Reference ranges for calcium sCT levels and CT thresholds in different groups of patients have been identified.     

Simplified patient-specific renal dosimetry in 177Lu therapy: a proof of concept

PurposeThe aim of this proof-of-concept study is to propose a simplified personalized kidney dosimetry procedure in ¹⁷⁷Lu peptide receptor radionuclide therapy (PRRT) for neuroendocrine tumors and metastatic prostate cancer. It relies on a single quantitative SPECT/CT acquisition and multiple radiometric measurements executed with a collimated external probe, properly directed on kidneys.MethodsWe conducted a phantom study involving external count-rate measurements in an abdominal phantom setup filled with activity concentrations of ^99mTc, reproducing patient-relevant organ effective half-lives occurring in ¹⁷⁷Lu PRRT. GATE Monte Carlo (MC) simulations of the experiment, using ^99mTc and ¹⁷⁷Lu as sources, were performed. Furthermore, we tested this method via MC on a clinical case of ¹⁷⁷Lu-DOTATATE PRRT with SPECT/CT images at three time points (2, 20 and 70 hrs), comparing a simplified kidney dosimetry, employing a single SPECT/CT and probe measurements at three time points, with the complete MC dosimetry.ResultsThe experimentally estimated kidney half-life with background subtraction applied was compatible within 3% with the expected value. The MC simulations of the phantom study, both with ^99mTc and ¹⁷⁷Lu, confirmed a similar level of accuracy. Concerning the clinical case, the simplified dosimetric method led to a kidney dose estimation compatible with the complete MC dosimetry within 6%, 12% and 2%, using respectively the SPECT/CT at 2, 20 and 70 hrs.ConclusionsThe proposed simplified procedure provided a satisfactory accuracy and would reduce the imaging required to derive the kidney absorbed dose to a unique quantitative SPECT/CT, with consequent benefits in terms of clinic workflows and patient comfort.     

Evaluation of Body Composition in Patients With and Without Adrenal Tumors and Without Overt Hypersecretory Syndromes

ObjectiveTo compare body composition between patients with autonomous cortisol secretion (ACS), those with nonfunctioning adrenal incidentalomas (NFAIs), and control subjects without adrenal tumors.MethodsA cross-sectional study was performed, incluidng the following 3 groups: patients with ACS (cortisol post–dexamethasone suppression test [DST] >1.8 μg/dL), NFAIs (cortisol post-DST ≤ 1.8 μg/dL), and patients without adrenal tumors (control group). Patients of the 3 groups were matched according to age (±5 years), sex, and body mass index (±5 kg/m²). Body composition was evaluated by bioelectrical impedance and abdominal computed tomography (CT) and urinary steroid profile by gas chromatography mass spectrometry.ResultsThis study enrolled 25 patients with ACS, 24 with NFAIs, and 24 control subjects. Based on CT images, a weak positive correlation between the serum cortisol level post-DST and subcutaneous fat area (r = 0.3, P =.048) was found. As assessed by bioelectrical impedance, lean mass and bone mass were positively correlated with the excretion of total androgens (r = 0.56, P <.001; and r = 0.58, P <.001, respectively); visceral mass was positively correlated with the excretion of glucocorticoid metabolites and total glucocorticoids (r = 0.28, P =.031; and r = 0.42, P =.001, respectively). Based on CT imaging evaluation, a positive correlation was observed between lean mass and androgen metabolites (r = 0.30, P =.036) and between visceral fat area, total fat area, and visceral/total fat area ratio and the excretion of glucocorticoid metabolites (r = 0.34, P =.014; r = 0.29, P =.042; and r = 0.31, P =.170, respectively).ConclusionThe urinary steroid profile observed in adrenal tumors, comprising a low excretion of androgen metabolites and high excretion of glucocorticoid metabolites, is associated with a lower lean mass and bone mass and higher level of visceral mass in patients with adrenal tumors.