Novel magnetic embolic MRI imageable particles with anticancer drug release for transcatheter arterial embolization and magnetic ablation.

The aim of the study is to prepare embolic hydroxyl ethyl cellulose (HEC)-polyvinyl prolidone (PVP)-magnetic particles suitable for transcatheter arterial chemoembolization (TACE) procedures, drug delivery, and magnetic hyperthermia. Two different sizes (microsized and nanosized) of iron oxide particles were used to prepare the embolic particles to investigate the embolization and drug delivery properties. Iron oxides were linked with PVP via bridging flocculation process, then outermost layer of the linked particles was coated with HEC in order to load drugs to particles and reach size requirements for a successful TACE procedure. Size of each particle was calibrated to the range that allows easy injections through microcatheters (40-500 µm). The results showed that the size of the final embolic particles reached around 70 µm with 82 W/g specific absorption rate (SAR) values for nano-iron oxide particles and 45 µm with 77 W/g SAR values for micro-iron oxide particles, which are quite suitable for TACE applications. Furthermore, an anticancer drug doxorubicin (DOX) was successfully loaded onto these particles in order to achieve localized chemotherapy at the tumor site. Particles produced in this study, loaded DOX successfully and prolonged drug release time, performed similarly to pure DOX at higher concentration treatments against human breast cancer cell lines, were heatable under applied alternating magnetic fields. In addition, in vivo embolization studies performed using a rabbit renal embolization model, indicated that these particles were easily delivered through microcatheters and were able to embolize the target.

Preliminary study: myocardial T1 relaxation time in patients with ischemic findings and normal findings on coronary angiography.

OBJECTIVE: The aim of this study is to evaluate the myocardium structure in patients with chest pain who were determined to have moderate and/or high risk for cardiac ischemic heart disease (IHD) but who had normal findings on conventional coronary angiography by using native cardiac magnetic resonance imaging (CMRI) T1 mapping and comparing with healthy volunteers. METHODS: A total of 50 patients and 30 healthy volunteers who underwent CMRI were included in our prospective study. Patients whose clinical findings were compatible with stable angina pectoris, with moderate and/or high risk for IHD, but whose conventional coronary angiography was normal, were our patient group. Native T1 values were measured for 17 myocardial segments (segmented based on American Heart Association recommendations) by two radiologists independently. The data obtained were statistically compared with the sample t-test. RESULTS: Myocardial native T1 values were found to be significantly prolonged in the patient group compared with the control group (p<0.05). Inter-observer reliability for native T1 value measurements of groups was high for both patient and control groups (α = 0.92 for the patient group and 0.96 for the control group). CONCLUSION: Findings suggestive of ischemia were detected by T1 mapping in the myocardium of our patients. For this reason, it is recommended that this patient group should be included in early diagnosis and close follow-up assessments for IHD.

The relationship between lesion density change in chest computed tomography and clinical improvement in COVID-19 patients.

OBJECTIVE: To evaluate the association of changes in chest computed tomography (CT) lesion densities with clinical improvement in COVID-19 patients. METHODS: This was a cross-sectional analysis of hospitalised COVID-19 patients who underwent repeated chest CT. Patients who improved clinically but showed radiological progression were included. Demographic data, presentation complaints and laboratory results were retrieved from the electronic database of the hospital. Lesion density that was measured in Hounsfield units was compred between admission and discharge chest CT scans. RESULTS: Forty patients (21 males, mean age 47.4 ± 15.1 years) were included in the analysis. The median white blood cell count and C-reactive protein significantly decreased, whereas the median lymphocyte count significantly increased at discharge compared with the admission values. The mean density significantly reduced from admission to discharge. CONCLUSION: This is the first study in the literature reporting reduction in chest CT lesion densities correlated with clinical and laboratory improvement in COVID-19 patients.

Transarterial Embolization of Liver Cancer in a Transgenic Pig Model.

PURPOSE: To develop and characterize a porcine model of liver cancer that could be used to test new locoregional therapies. MATERIALS AND METHODS: Liver tumors were induced in 18 Oncopigs (transgenic pigs with Cre-inducible TP53R167H and KRASG12D mutations) by using an adenoviral vector encoding the Cre-recombinase gene. The resulting 60 tumors were characterized on multiphase contrast-enhanced CT, angiography, perfusion, micro-CT, and necropsy. Transarterial embolization was performed using 40-120 µm (4 pigs) or 100-300 µm (4 pigs) Embosphere microspheres. Response to embolization was evaluated on imaging. Complications were determined based on daily clinical evaluation, laboratory results, imaging, and necropsy. RESULTS: Liver tumors developed at 60/70 (86%) inoculated sites. Mean tumor size was 2.1 cm (range, 0.3-4 cm) at 1 week. Microscopically, all animals developed poorly differentiated to undifferentiated carcinomas accompanied by a major inflammatory component, which resembled undifferentiated carcinomas of the human pancreatobiliary tract. Cytokeratin and vimentin expression confirmed epithelioid and mesenchymal differentiation, respectively. Lymph node, lung, and peritoneal metastases were seen in some cases. On multiphase CT, all tumors had a hypovascular center, and 17/60 (28%) had a hypervascular rim. After transarterial embolization, noncontrast CT showed retained contrast medium in the tumors. Follow-up contrast-enhanced scan showed reduced size of tumors after embolization using either 40-120 µm or 100-300 µm Embosphere microspheres, while untreated tumors showed continued growth. CONCLUSIONS: Liver tumors can be induced in a transgenic pig and can be successfully treated using bland embolization.

A dual-modal PET/near infrared fluorescent nanotag for long-term immune cell tracking.

Adoptive cell transfer of targeted chimeric antigen receptor (CAR) T cells has emerged as a highly promising cancer therapy. The pharmacodynamic action or CAR T cells is closely related to their pharmacokinetic profile; because of this as well as the risk of non-specific action, it is important to monitor their biodistribution and fate following infusion. To this end, we developed a dual-modal PET/near infrared fluorescent (NIRF) nanoparticle-based imaging agent for non-genomic labeling of human CAR T cells. Since the PET/NIRF nanoparticles did not affect cell viability or cytotoxic functionality and enabled long-term whole-body CAR T cell tracking using PET and NIRF in an ovarian peritoneal carcinomatosis model, this platform is a viable imaging technology to be applied in other cancer models.

Postmortem Biopsies of the Lung, Heart, Liver, and Spleen of COVID-19 Patients.

Objective We aimed to evaluate histopathologic alterations in the lung, heart, liver, and spleen of coronavirus disease 2019 (COVID-19) decedents through postmortem core needle biopsies. Materials and methods Patients who died of reverse transcription-polymerase chain reaction-proven COVID-19 were included in this postmortem case series. Postmortem percutaneous ultrasound-guided biopsies of the lungs, heart, liver, and spleen were performed using 14- and 16-gauge needles. Biopsy samples were stained with hematoxylin-eosin and examined under a light microscope. Clinicodemographic characteristics, chest computed tomography (CT) images, and COVID-19-related treatments of the patients were also collected. Results Seven patients were included in this study. Liver and heart tissue samples were available from all patients, and lung and spleen tissue samples were available from five and three patients, respectively. Chest CT images predominantly revealed bibasilar ground-glass opacities. Lung biopsies showed diffuse alveolar damage in all biopsy specimens. Heart findings were nonspecific and largely compatible with the underlying disease. Patchy necrosis, steatosis, and mononuclear cell infiltration were the main findings in the liver biopsies. Splenic histopathological examination showed that splenic necrosis and neutrophil infiltration were common findings in all patients. Conclusion Tissue acquisition was complete for the heart and liver and acceptable for the lungs. The amount of tissue was sufficient for a proper histopathologic examination. Histopathological findings were generally in accordance with previous autopsy studies. Radiological findings of the lung were also correlated with the histopathologic findings. We consider that a postmortem biopsy is a feasible alternative for histopathological examinations in COVID-19 decedents.

Induction and characterization of pancreatic cancer in a transgenic pig model.

BACKGROUND: Preclinical testing of new locoregional therapies for pancreatic cancer has been challenging, due to the lack of a suitable large animal model. PURPOSE: To develop and characterize a porcine model of pancreatic cancer. Unlike small animals, pigs have similar physiology, drug dosing, and immune response to humans. Locoregional therapy in pigs can be performed using the same size catheters and devices as in humans. METHODS: The Oncopig is a transgenic pig with Cre-inducible TP53R167H and KRASG12D mutations. In 12 Oncopigs, CT-guided core biopsy of the pancreas was performed. The core biopsy was incubated with an adenoviral vector carrying the Cre recombinase gene. The transformed core biopsy was injected back into the pancreas (head, tail, or both). The resulting tumors (n = 19) were characterized on multi-phase contrast-enhanced CT, and on pathology, including immunohistochemistry. Angiographic characterization of the tumors was performed in 3 pigs. RESULTS: Pancreatic tumors developed at 19 out of 22 sites (86%) that were inoculated. Average tumor size was 3.0 cm at 1 week (range: 0.5-5.1 cm). H&E and immunohistochemical stains revealed undifferentiated carcinomas, similar to those of the pancreatobiliary system in humans. Neoplastic cells were accompanied by a major inflammatory component. 1 of 12 pigs only had inflammatory nodules without evidence of neoplasia. On multiphase CT, tumors were hypovascular compared to the normal pancreas. There was no pancreatic duct dilation. In 3 pigs, angiography was performed, and in all 3 cases, the artery supplying the pancreatic tumor could be catheterized using a 2.4 F microcatheter. Selective angiography showed the pancreatic tumor, without extra-pancreatic perfusion. CONCLUSION: Pancreatic cancer can be induced in a transgenic pig. Intra-arterial procedures using catheters designed for human interventions were technically feasible in this large animal model.

One-Step, Rapid, 18F-19F Isotopic Exchange Radiolabeling of Difluoro-dioxaborinins: Substituent Effect on Stability and In Vivo Applications.

The ß-diketone moiety is commonly present in many anticancer drugs, antibiotics, and natural products. We describe a general method for radiolabeling ß-diketone-bearing molecules with fluoride-18. Radiolabeling was carried out via 18F-19F isotopic exchange on nonradioactive difluoro-dioxaborinins, which were generated by minimally modifying the ß-diketone as a difluoroborate. Radiochemistry was one-step, rapid (<10 min), and high-yielding (>80%) and proceeded at room temperature to accommodate the half-life of F-18 (t1/2 = 110 min). High molar activities (7.4 Ci/µmol) were achieved with relatively low starting activities (16.4 mCi). It was found that substituents affected both the solvolytic stability and fluorescence properties of difluoro-dioxaborinins. An F-18 radiolabeled difluoro-dioxaborinin probe that was simultaneously fluorescent showed sufficient stability for in vivo positron emission tomography (PET)/fluorescence imaging in mice, rabbits, and patients. These findings will guide the design of probes with specific PET/fluorescence properties; the development of new PET/fluorescence dual-modality reporters; and accurate in vivo tracking of ß-diketone molecules.

Accuracy of Multi-echo Dixon Sequence in Quantification of Hepatic Steatosis.

Objective Today, a biopsy is the gold standard in the diagnosis of non-alcoholic fatty liver. However, a biopsy is an invasive technique, limited to the sample taken, and it may lead to misdiagnosis. Therefore, novel noninvasive options are needed. The objective of this study was to investigate the accuracy of magnetic resonance (MR) Dixon sequence and elastography using magnetic resonance spectroscopy (MRS) as a reference in the quantification of hepatic steatosis. Methods A total of 60 patients were included in the study. All patients underwent magnetic resonance imaging (MRI), MRS, and elastography in order to quantify hepatosteatosis. MRI and MRS imaging studies were performed using MR Dixon and high-speed T2-corrected multiple-echo 1H-MRS sequence (HISTO) sequences, respectively, in order to calculate proton density fat fraction (PDFF) values. Results The mean MRI-PDFF value with the MRS region of interest (ROI) was found as 9.4% ± 12.1%. The mean MRS-PDFF was found as 8.9% ± 11.3%. No statistically significant difference was found between MRS-PDFF and MRI-PDFF values measured in ROI (p < 0.005). The correlation between MRS-PDFF and MRI-PDFF was examined with Spearman's correlation analysis. Accordingly, there was an excellent correlation between MRS and MRI values measured in ROI (r ≥ 0.8, p < 0.001). Sensitivity, specificity, positive predictive value, and negative predictive value were calculated as 96%, 100%, 89.5%, and 92.6%, respectively, for MRI-PDFF in predicting hepatic steatosis for the same ROI localization with MRS. The optimum cut-off value of MRS-PDFF in predicting hepatic steatosis was found as 5.3% using the same ROI localization with MRS. Conclusion The results of this study indicated an excellent correlation between MRI-PDFF and MRS-PDFF. The multi-echo Dixon MRI technique seems a promising alternative method in the detection of non-alcoholic fatty liver disease.

Success and reliability of extrafemoral Exoseal vascular closure device: "Off-label" usage.

Aim: The aim of this study is to present the reliability and efficacy of Exoseal vascular closure device (EVCD) for closure of extrafemoral punctures. Materials and methods: All patients who were treated with EVCD following arterial endovascular treatment involving an extrafemoral puncture between April 2013 and January 2014 were examined retrospectively. This study included 11 patients (4 women and 7 men between the ages of 48 and 87 years; average age = 65 years). A total of 13 procedures were performed in 11 patients involving the following access routes: brachial artery (n = 5), popliteal artery (n = 4), and polytetrafluoroethylene graft (n = 4). Results: Twelve out of 13 EVCD procedures achieved technical success and procedural success. One minor and one major complications occurred. Both complications were revealed to be pseudoaneurysms, both in the brachial artery. Pseudoaneurysm of the minor complication was treated by Fibrin Sealant (Tisseel) injection guided by ultrasonography and the other pseudoaneurysm was treated by covered stent placement. Conclusions: The femoral artery is an essential access route of arterial endovascular procedures; however, in some cases, the extrafemoral arterial route is necessary. In this study, EVCD was found to be useful for closing extrafemoral arterial routes. This study had a limited number of cases and more large-scale studies are needed.

Measurement of spinal root angle at spinal canal and foraminal levels in cases of facet arthropathy: T2-weighted turbo spin echo magnetic resonance myelography with SPACE technique.

BACKGROUND: Magnetic resonance myelography (MRM) with three-dimensional (3D) T2-weighted (T2W) turbo spin echo (TSE) sampling perfection with application-optimized contrasts using different flip angle evolution (SPACE) may be a guide to the etiology of low back pain. PURPOSE: To research the efficiency of a 3D T2W TSE SPACE MRM sequence for visualization of anatomic details of spinal nerve root at the spinal canal and lateral recess levels in the patients with low back pain. MATERIAL AND METHODS: Lumbar spinal MRM 3D T2W TSE SPACE was performed in a total of 70 patients (median age 46 years). Patients were imaged while lying in a supine position with straightened legs. According to the degree of facet arthropathy findings, patients were divided into four separate subgroups in our retrospective cross-sectional study. Spinal nerve root angle was measured within the spinal canal and at lateral recess level, and facet joint angle and lumbar lordosis measurements were measured by two radiologists, independently. RESULTS: Lumbar level was strongly negatively correlated with facet joint angle (r = -0.95) as well as nerve root angle within the spinal canal (NRASC) (r = -0.857) and at the lateral recess level (NRALR) (r = -0.947). Intracanal decline of the spinal root angle caused by spinal stenosis findings was also observed (P < 0.05). For the measurements of NRASC and NRALR, inter-observer correlation was 0.85 and 0.82 for the spinal canal and at lateral recess level, respectively. CONCLUSION: 3D T2W SPACE in NRASC and NRALR provided high resolution images for evaluation. Therefore, this method may be a qualitative guide for the clinician and the surgeon in terms of root anatomy before any intervention.

A Fluorescent, [18F]-Positron-Emitting Agent for Imaging Prostate-Specific Membrane Antigen Allows Genetic Reporting in Adoptively Transferred, Genetically Modified Cells.

Clinical trials involving genome-edited cells are growing in popularity, where CAR-T immunotherapy and CRISPR/Cas9 editing are more recognized strategies. Genetic reporters are needed to localize the molecular events inside these cells in patients. Specifically, a nonimmunogenic genetic reporter is urgently needed as current reporters are immunogenic due to derivation from nonhuman sources. Prostate-specific membrane antigen (PSMA) is potentially nonimmunogenic due to its natural, low-level expression in select tissues (self-MHC display). PSMA overexpression on human prostate adenocarcinoma is also visible with excellent contrast. We exploit these properties in a transduced, two-component, Human-Derived, Genetic, Positron-emitting, and Fluorescent (HD-GPF) reporter system. Mechanistically analogous to the luciferase and luciferin reporter, PSMA is genetically encoded into non-PSMA expressing 8505C cells and tracked with ACUPA-Cy3-BF3, a single, systemically injected small molecule that delivers positron emitting fluoride (18F) and a fluorophore (Cy3) to report on cells expressing PSMA. PSMA-lentivirus transduced tissues become visible by Cy3 fluorescence, [18F]-positron emission tomography (PET), and γ-scintillated biodistribution. HD-GPF fluorescence is visible at subcellular resolution, while a reduced PET background is achieved in vivo, due to rapid ACUPA-Cy3-BF3 renal excretion. Co-transduction with luciferase and GFP show specific advantages over popular genetic reporters in advanced murine models including, a "mosaic" model of solid-tumor intratumoral heterogeneity and a survival model for observing postsurgical recurrence. We report an advanced genetic reporter that tracks genetically modified cells in entire animals and with subcellular resolution with PET and fluorescence, respectively. This reporter system is potentially nonimmunogenic and will therefore be useful in human studies. PSMA is a biomarker of prostate adenocarcinoma and ACUPA-Cy3-BF3 potential in radical prostatectomy is demonstrated.

The ghrelin and orexin activity in testicular tissues of patients with idiopathic non-obstructive azoospermia.

The aim of the present study is to evaluate the presence of ghrelin and orexin in the testicular tissue of patients who have undergone microscopic testicular sperm extraction (micro-TESE) due to idiopathic non-obstructive azoospermia. Seventy azoospermic cases were included in this study; serum hormone levels were measured and genetic investigations were performed. The patients were divided into two groups: micro-TESE (+) and micro-TESE (-). The number of Leydig cells and stained cells in the seminiferous tubules were counted under a light microscope, and we analyzed ghrelin and orexin activity. The relationship between serum hormone levels and ghrelin and orexin distributions in testicular tissue was evaluated according to micro-TESE results. While sperm was found in 33 cases (47.1%), micro-TESE was negative in 37 cases (52.9%). Peptide hormone activity in testicular tissue was higher in micro-TESE (+) cases. However, interstitial orexin (p = 0.038) and ghrelin (p = 0.002) activity showed statistically meaningful differences. Many different peptides, genes, and other unknown mechanisms play important roles in testicular function. In particular, the peptides orexin and ghrelin may play regulatory roles in testicular function in humans.

An in-vivo pilot study into the effects of FDG-mNP in cancer in mice.

PURPOSE: Previously, fluorodeoxy glucose conjugated magnetite nanoparticles (FDG-mNPs) injected into cancer cells in conjunction with the application of magnetic hyperthermia have shown promise in new FDG-mNPs applications. The aim of this study was to determine potential toxic or unwanted effects involving both tumour cells and normal tissue in other organs when FDG-mNPs are administered intravenously or intratumourally in mice. MATERIALS AND METHODS: FDG-mNPs were synthesized. A group of six prostate-tumour bearing mice were injected with 23.42 mg/ml FDG-mNPs (intravenous injection, n = 3; intratumoural injection into the prostate tumour, n = 3). Mice were euthanized and histological sampling of tissue was conducted for the prostate tumour, as well as for lungs, lymph nodes, liver, kidneys, spleen, and brain, at 1 hour (n = 2) and 7 days (n = 4) post-injection. A second group of two normal (non-cancerous) mice received the same injection intravenously into the tail vein and were euthanised at 3 and 6 months post-injection, respectively, to investigate if FDG-mNPs remained in organs at those time points. RESULTS: In prostate-tumour bearing mice, FDG-mNPs concentrated in the prostate tumour, while relatively small amounts were found in the organs of other tissues, particularly the spleen and the liver; FDG-mNP concentrations decreased over time in all tissues. In normal mice, no detrimental effects were found in either mouse at 3 or 6 months. CONCLUSION: Intravenous or intratumoural FDG-mNPs can be safely administered for effective cancer cell destruction. Further research on the clinical utility of FDG-mNPs will be conducted by applying hyperthermia in conjunction with FDG-mNPs in mice.

18F-Positron Emitting/Trimethine Cyanine-Fluorescent Contrast for Image-Guided Prostate Cancer Management.

[18/19F]-4, an anionic GCPII/PSMA inhibitor for image-guided intervention in prostate cancer, is described. [19F]-4 is radiolabeled with a radiochemical yield that is ≥27% and a molar activity of 190 ± 50 mCi/µmol in a <1 h, one-step, aqueous isotopic exchange reaction. [19F]-4 allows PSMA expression to be imaged by fluorescence (FL) and [18F]-PET. PC3-PIP (PSMA-positive, EC50 = 6.74 ± 1.33 nM) cancers are specifically delineated in mice that bear 3 million (18 mg) PC3-PIP and PC3 (control, PSMA-negative) cells. Colocalization of [18/19F]-4 PET, fluorescence, scintillated biodistribution, and PSMA expression are observed.

A new method for computer-assisted detection, definition and differentiation of the urinary calculi.

PURPOSE: Urinary stones are common and can be diagnosed with computed tomography (CT) easily. In this study, we aimed to specify the opacity characteristics of various types of calcified foci that develop through the urinary system by using an image analysis program. With this method, we try to differentiate the calculi from the non-calculous opacities and also we aimed to present how to identify the characteristic features of renal and ureteral calcules. MATERIALS AND METHODS: We obtained the CT studies of the subjects (n = 48, mean age = 41 years) by using a dual source CT imaging system. We grouped the calculi detected in the dual-energy CT sections as renal (n = 40) or ureteric (n = 45) based on their locations. Other radio-opaque structures that were identified outside but within close proximity of the urinary tract were recorded as calculi "mimickers". We used ImageJ program for morphological analysis. All the acquired data were analyzed statistically. RESULTS: According to thorough morphological parameters, there were statistically significant differences in the angle and Feret angle values between calculi and mimickers (p < 0.001). Multivariate logistical regression analysis showed that Minor Axis and Feret angle parameters can be used to distinguish between ureteric (p = 0.003) and kidney (p = 0.001) stones. CONCLUSIONS: Computer-based morphologic parameters can be used simply to differentiate between calcular and noncalcular densities on CT and also between renal and ureteric stones.

Small bowel intussusception in a pregnant woman with Peutz-Jeghers Syndrome.

Intussusception is the most frequent complication of Peutz-Jeghers Syndrome (PJS), but usually seen in child age. It is a predictable, but infrequent complication in adults with PJS. However, there is no report about intussusception in pregnancy period secondary to Peutz-Jeghers (PJ) polyps in the literature. In this paper, we present a rare intussusception case in a pregnant woman with PJS, which was diagnosed with magnetic resonance imaging, and discuss this condition with a brief literature review.