Safety and Biodistribution of an Autologous Bone Marrow-Derived Mononuclear Cell Infusion into Renal Arteries in Patients with Focal Segmental Glomerulosclerosis: A Phase 1 Study.

Patients with focal segmental glomerulosclerosis (FSGS) who are refractory to drug treatment may present progressive loss of kidney function, leading to chronic kidney disease stage 5 under dialysis treatment. The safety of systemic administration of bone marrow-derived mononuclear cells (BMDMCs) has been shown in different preclinical models of kidney diseases. However, to date, no study has evaluated the safety and biodistribution of BMDMCs after infusion in renal arteries in patients with FSGS. We used a prospective, non-randomized, single-center longitudinal design to investigate this approach. Five patients with refractory FSGS and an estimated glomerular filtration rate (eGFR) between 20 and 40 ml/min/1.73 m2 underwent bone marrow aspiration and received an arterial infusion of autologous BMDMCs (5 × 107) for each kidney. In addition, BMDMCs labeled with technetium-99m (99mTc-BMDMCs) were used to assess the biodistribution by scintigraphy. All patients completed the 270-day follow-up protocol with no serious adverse events. A transient increase in creatinine was observed after the cell therapy, with improvement on day 30. 99mTc-BMDMCs were detected in both kidneys and counts were higher after 2 hr compared with 24 hr. The arterial infusion of BMDMCs in both kidneys of patients with FSGS was considered safe with stable eGFR at the end of follow-up. This trial is registered with NCT02693366.

Superficial Femoral Artery in-Stent Restenosis Treated with Paclitaxel-Coated Balloon Angioplasty - Results of Three-Year Follow-Up.

BACKGROUND: In-stent restenosis remains a common and important complication after endovascular treatment of superficial femoral artery peripheral artery disease. It occurs in 14 to 35% of cases in 1 year and there is still no efficient treatment for this condition. Paclitaxel-coated balloons have shown promising results. OBJECTIVE: Investigate the 3 year results of superficial femoral artery in-stent restenosis treated with paclitaxel-coated balloon angioplasty, using the Lutonix™ 035 device. METHODS: We conducted a retrospective observational study with patients with symptomatic (Rutherford 2 to 5) superficial femoral artery in-stent restenosis, that were treated with paclitaxel-coated balloon angioplasty using the Lutonix™ 035 device, in a single center from January 2016 to December 2020. Duplex scan was used to follow the patients. Primary patency was obtained through Kaplan-Meier analysis. Mortality, and amputation rates were also evaluated. RESULTS: 105 patients were included. Two patients had technical failure and required an additional stent, and were thus excluded. 103 patients were analyzed. Primary patency was 91.26, 80.47, and 67.71%, respectively, in the first, second, and third year after the procedure. There were no deaths 30 days after the procedure. There were no major amputations during the 3 year follow-up. CONCLUSION: Paclitaxel-coated balloon angioplasty with the Lutonix™ 035 device was a safe and effective treatment to superficial femoral artery in-stent restenoses. The results were maintained along the 3 year follow-up.

The Use of 99mTc-Mononuclear Leukocyte Scintigraphy for Necrotizing External Otitis Diagnosis.

BACKGROUND: Necrotizing external otitis (NEO) is a severe infectious disease in the external acoustic meatus (EAM) and mastoid that may extend to the cranial base. Due to the lack of a gold standard examination technique, the diagnosis is often difficult and delayed. This study aimed to evaluate the sensitivity and specificity of 99mTc-mononuclear leukocyte scintigraphy associated with 99mTc-phytate in suspected NEO compared to 99mTc-MDP and 67Ga-citrate. METHODS: A prospective study (32 patients) was conducted between 2011 and 2016. RESULTS: At the end, twenty-four patients remained for the study conduction; nineteen had confirmed NEO diagnosis, one had sarcoma, one had EAM cholesteatoma, one had diffuse simple external otitis, and two had an inconclusive diagnosis. 99mTc-mononuclear leukocyte scintigraphy plus 99mTc-phytate was as sensitive as 99mTc-MDP bone scintigraphy (19/19X9/19), and more sensitive than 67Ga scintigraphy (19/19 x 17/19). Regarding specificity, it was superior to bone scintigraphy, 100% × 40% (5/5 × 2/5), and 67Ga scintigraphy, 100% × 20% (5/5 × 1/5). After the infection resolution, all NEO patients had their leukocyte scintigraphy negativized. To the best of our knowledge, this is the first study that evaluates this technique in patients with suspected NEO. CONCLUSIONS: 99mTc-mononuclear leukocyte was revealed to be the best option for NEO because of its specificity.

The Use of 99mTc-Labeled Stem Cells for Evaluation of Chronic Kidney Disease.

The labeling of stem cells with radionuclides allows in vivo monitoring of cell migration and homing. Here, we describe the labeling of mononuclear stem cells with 99mTc and show their biodistribution in preclinical models and patients with chronic kidney disease.

Granulocyte Colony-Stimulating Factor Treatment Before Radiotherapy Protects Against Radiation-Induced Liver Disease in Mice.

Radiation-induced liver disease (RILD) remains a major problem resulting from radiotherapy. In this scenario, immunotherapy with granulocyte colony-stimulating factor (G-CSF) arises as an attractive approach that might improve the injured liver. Here, we investigated G-CSF administration's impact before and after liver irradiation exposure using an association of alcohol consumption and local irradiation to induce liver disease model in C57BL/6 mice. Male and female mice were submitted to a previous alcohol-induced liver injury protocol with water containing 5% alcohol for 90 days. Then, the animals were treated with G-CSF (100 µg/kg/d) for 3 days before or after liver irradiation (18 Gy). At days 7, 30, and 60 post-radiation, non-invasive liver images were acquired by ultrasonography, magnetic resonance, and computed tomography. Biochemical and histological evaluations were performed to verify whether G-CSF could prevent liver tissue damage or reverse the acute liver injury. Our data showed that the treatment with G-CSF before irradiation effectively improved morphofunctional parameters caused by RILD, restoring histological arrangement, promoting liver regeneration, preserving normal organelles distribution, and glycogen granules. The amount of OV-6 and F4/80-positive cells increased, and α-SMA positive cells' presence was normalized. Additionally, prior G-CSF administration preserved serum biochemical parameters and increased the survival rates (100%). On the other hand, after irradiation, the treatment showed a slight improvement in survival rates (79%) and did not ameliorate RILD. Overall, our data suggest that G-CSF administration before radiation might be an immunotherapeutic alternative to radiotherapy planning to avoid RILD.

Limb ischemia in patients with COVID-19.

This narrative review covers the life-threatening thromboembolic events associated with SARS-CoV-2 infection/COVID-19. It addresses the physical changes that cause vascular and arterial damage to limbs, laboratory management of coagulation, and management of anticoagulation. COVID-19's relationship with deep venous thrombosis and arterial thrombosis is also emphasized. The main thromboembolic events described in the literature are illustrated with examples from our experience with COVID-19 patients.

Esta revisão narrativa abrange os eventos tromboembólicos com risco de vida associados a infecção por SARS-CoV-2/COVID-19. Aborda as mudanças físicas que causam danos vasculares e arteriais aos membros, o manejo laboratorial da coagulação e o manejo da anticoagulação. A relação de COVID-19 com trombose venosa profunda e trombose arterial também é enfatizada. Os principais eventos tromboembólicos descritos na literatura são ilustrados a partir de nossa experiência com pacientes COVID-19.

Should We Scan Hidradenitis Suppurativa Patients? A Systematic Review of Radiologic Findings.

OBJECTIVE: To bring awareness and close gaps between dermatologists and radiologists about the contribution of imaging techniques for diagnosis, treatment, and follow-up of hidradenitis suppurativa (HS). DATA SOURCES: Investigators searched the PubMed database for articles on HS and radiology techniques. STUDY SELECTION: Databases were searched up to December 2018. The query retrieved 257 publications, of which 103 were unique; of these, 7 were inaccessible. From the remaining 96, 33 were irrelevant (did not discuss HS lesion features). After applying the inclusion criteria, 63 studies were relevant to this study. DATA EXTRACTION: A standardized form was constructed to extract data from eligible studies by two independent authors. DATA SYNTHESIS: Imaging techniques are significant and useful tools in HS management. Imaging should be carried out to evaluate disease severity, subclinical features, treatment success, and intraoperative patient assessment. Providers should consider nonconventional radiology techniques, which are underused in clinical management of HS. Further, dermatology and radiology require a shared terminology of disease features to better understand patient status. CONCLUSIONS: Publications on HS lesion imaging have increased over the years. Imaging techniques have proven useful for determining HS severity and treatment effectiveness, as well as intraoperative patient assessment. These authors strongly recommend the use of these techniques in routine clinical practice for patients with HS.

99mTc-antitumor necrosis factor-alpha scintigraphy for the detection of inflammatory activity in rheumatoid arthritis.

OBJECTIVE: Tumor necrosis factor-alpha (TNF-α) is an important inflammatory cytokine. 99mTc-anti-TNF-α antibody scintigraphy has proven to be a viable alternative to MRI in specific cases. The objective of this study was to evaluate the performance of scintigraphy with 99mTc-anti-TNF-α in the identification of inflammatory foci in individuals diagnosed with rheumatoid arthritis using MRI as the gold standard. METHODS: This cross-sectional, descriptive and analytical-qualitative clinical study compared the performance of 99mTc-anti-TNF-α scintigraphy with that of MRI with intravenous administration of gadolinium (used as the gold standard) and a clinical examination (Disease Activity Score 28) in 220 joints of 20 patients with a diagnosis of rheumatoid arthritis and one healthy control. RESULTS: The concordance of scintigraphy with MRI in individuals with a diagnosis of rheumatoid arthritis was 79%. The accuracy, sensitivity and specificity of scintigraphy for distinguishing between inflammatory and noninflammatory sites were 92, 89, and 93%, respectively. No adverse reactions to the examinations were reported. CONCLUSIONS: Scintigraphy with 99mTc-anti-TNF-α was well-tolerated and had a good ability to distinguish between inflammatory and noninflammatory lesions in patients with rheumatoid arthritis.

Limb ischemia in patients with COVID-19 / Isquemia de membros em pacientes com COVID-19

Abstract This narrative review covers the life-threatening thromboembolic events associated with SARS-CoV-2 infection/COVID-19. It addresses the physical changes that cause vascular and arterial damage to limbs, laboratory management of coagulation, and management of anticoagulation. COVID-19's relationship with deep venous thrombosis and arterial thrombosis is also emphasized. The main thromboembolic events described in the literature are illustrated with examples from our experience with COVID-19 patients.

Resumo Esta revisão narrativa abrange os eventos tromboembólicos com risco de vida associados a infecção por SARS-CoV-2/COVID-19. Aborda as mudanças físicas que causam danos vasculares e arteriais aos membros, o manejo laboratorial da coagulação e o manejo da anticoagulação. A relação de COVID-19 com trombose venosa profunda e trombose arterial também é enfatizada. Os principais eventos tromboembólicos descritos na literatura são ilustrados a partir de nossa experiência com pacientes COVID-19.

IAEA contribution to the development of 64Cu radiopharmaceuticals for theranostic applications.

Copper-64 is a very attractive radioisotope with unique nuclear properties that allow using it as both a diagnostic and therapeutic agent, thus providing an almost ideal example of a theranostic radionuclide. A characteristic of Cu-64 stems from the intrinsic biological nature of copper ions that play a fundamental role in a large number of cellular processes. Cu-64 is a radionuclide that reflects the natural biochemical pathways of Cu-64 ions, therefore, can be exploited for the detection and therapy of certain malignancies and metabolic diseases. Beside these applications of Cu-64 ions, this radionuclide can be also used for radiolabelling bifunctional chelators carrying a variety of pharmacophores for targeting different biological substrates. These include peptide-based substrates and immunoconjugates as well as small-molecule bioactive moieties. Fueled by the growing interest of Member States (MS) belonging to the International Atomic Energy Agency (IAEA) community, a dedicated Coordinated Research Project (CRP) was initiated in 2016, which recruited thirteen participating MS from four continents. Research activities and collaborations between the participating countries allowed for collection of an impressive series of results, particularly on the production, preclinical evaluation and, in a few cases, clinical evaluation of various 64Cu-radiopharmaceuticals that may have potential impact on future development of the field. Since this CRP was finalized at the beginning of 2020, this short review summarizes outcomes, outputs and results of this project with the purpose to propagate to other MS and to the whole scientific community, some of the most recent achievements on this novel class of theranostic 64Cu-pharmaceuticals.

Development of 131I-ixolaris as a theranostic agent: metastatic melanoma preclinical studies.

Tissue factor (TF), a blood coagulation protein, plays an important role in tumor growth, invasion, and metastasis. Ixolaris, a tick-derived non-immunogenic molecule that binds to TF, has demonstrated in vivo inhibitory effect on murine models of melanoma, including primary growth and metastasis. This work aimed to: I) develop an efficient and stable labeling technique of ixolaris with Iodine-131(131I); II) compare the biodistribution of 131I and 131I-ixolaris in tumor-free and melanoma-bearing mice; III) evaluate whether 131I-ixolaris could serve as an antimetastatic agent. Ixolaris radioiodination was performed using iodogen, followed by liquid paper chromatography. Labeling stability and anticoagulant activity were measured. Imaging studies were performed after intravenous administration of free 131I or 131I-ixolaris in a murine melanoma model employing the B16-F10 cell line. Animals were divided in three experimental groups: the first experimental group, D0, received a single-dose of 9.25 MBq of 131I-ixolaris at the same day the animals were inoculated with melanoma cells. In the second group, D15, a single-dose of 9.25 MBq of 131I-ixolaris or free 131I was applied into mice on the fifteenth day after the tumor induction. The third group, D1-D15, received two therapeutic doses of 9.25 MBq of 131I-ixolaris or 131I. In vitro studies demonstrated that 131I-ixolaris is stable for up to 24 h and retains its inhibitory activity on blood coagulation. Biodistribution analysis and metastasis assays showed that all treatment regimens with 131I-ixolaris were effective, being the double-treatment (D1/D15) the most effective one. Remarkably, treatment with free 131I showed no anti-metastatic effect. 131I-ixolaris is a promising theranostic agent for metastatic melanoma.

Autologous bone marrow-derived mononuclear cell therapy in three patients with severe asthma.

BACKGROUND: Despite recent advances in understanding its pathophysiology and development of novel therapies, asthma remains a serious public health issue worldwide. Combination therapy with inhaled corticosteroids and long-acting ß2-adrenoceptor agonists results in disease control for many patients, but those who exhibit severe asthma are often unresponsive to conventional treatment, experiencing worse quality of life, frequent exacerbations, and increasing healthcare costs. Bone marrow-derived mononuclear cell (BMMC) transplantation has been shown to reduce airway inflammation and remodeling and improve lung function in experimental models of allergic asthma. METHODS: This is a case series of three patients who presented severe asthma, unresponsive to conventional therapy and omalizumab. They received a single intravenous dose of autologous BMMCs (2 × 107) and were periodically evaluated for 1 year after the procedure. Endpoint assessments included physical examination, quality of life questionnaires, imaging (computed tomography, single-photon emission computed tomography, and ventilation/perfusion scan), lung function tests, and a 6-min walk test. RESULTS: All patients completed the follow-up protocol. No serious adverse events attributable to BMMC transplantation were observed during or after the procedure. Lung function remained stable throughout. A slight increase in ventilation of the right lung was observed on day 120 after BMMC transplantation in one patient. All three patients reported improvement in quality of life in the early post-procedure course. CONCLUSIONS: This paper described for the first time the effects of BMMC therapy in patients with severe asthma, providing a basis for subsequent trials to assess the efficacy of this therapy.

Intravenous Human Umbilical Cord-Derived Mesenchymal Stromal Cell Administration in Models of Moderate and Severe Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) is as a life-threatening condition that can occur in young adults, often causing long-term disability. Recent preclinical data suggest mesenchymal stromal cell (MSC)-based therapies as promising options to minimize brain damage after ICH. However, therapeutic evidence and mechanistic insights are still limited, particularly when compared with other disorders such as ischemic stroke. Herein, we employed a model of collagenase-induced ICH in young adult rats to investigate the potential therapeutic effects of an intravenous injection of human umbilical cord Wharton's jelly-derived MSCs (hUC-MSCs). Two doses of collagenase were used to cause moderate or severe hemorrhages. Magnetic resonance imaging showed that animals treated with hUC-MSCs after moderate ICH had smaller residual hematoma volumes than vehicle-treated rats, whereas the cell therapy failed to decrease the hematoma volume in animals with a severe ICH. Functional assessments (rotarod and elevated body swing tests) were performed for up to 21 days after ICH. Enduring neurological impairments were seen only in animals subjected to severe ICH, but the cell therapy did not induce statistically significant improvements in the functional recovery. The biodistribution of Technetium-99m-labeled hUC-MSCs was also evaluated, showing that most cells were found in organs such as the spleen and lungs 24 h after transplantation. Nevertheless, it was possible to detect a weak signal in the brain, which was higher in the ipsilateral hemisphere of rats subjected to a severe ICH. These data indicate that hUC-MSCs have moderately beneficial effects in cases of less severe brain hemorrhages in rats by decreasing the residual hematoma volume, and that optimization of the therapy is still necessary.

Safety and Localization of Mesenchymal Stromal Cells Derived from Human Adipose Tissue-Associated Hyaluronic Acid: A Preclinical Study.

Millions of plastic surgeries are performed worldwide every year with the objective of correcting lipodystrophies stemming from lesions, tumor resections, birth defects, and AIDS-associated antiretroviral therapy. Besides that, a large number of clinical research have assessed the outcome of procedures that rely on combinations of dermal fillers and autologous cells. However, little is known about the safety of these combinations and the localization of the injected cells. The aim of this study was to test the toxicity of a solution containing 1% hyaluronic acid (HA) and adipose-derived stromal cells (ASCs) from the human adipose tissue and to assess the localization of the injected cells, with and without HA, labeled with technetium-99m. Rats received subcutaneous and intraperitoneal injections of a solution containing 1% HA/adipose-derived stromal cells isolated from the human fat tissue. The animals were then observed for up to forty-two days. The solution tested in this study did not result in systemic, biochemical, or anatomic alterations that could represent toxicity symptoms. The association of HA and ASCs labeled with technetium-99m remained at the site of the injection within a period of twenty-four hours, as demonstrated by a whole-body imaging software fusion of SPECT and CT. In conclusion, our study shows that the subcutaneous and intraperitoneal injection of HA associated with adipose-derived stromal cells (ASCs) is safe. The association of HA and ASCs did not induce local or systemic toxicity. Thus, the administration of volume equal to or less than 0.2 mL of the agent filler (1 × 106 ASC+HA 1%) should be considered for subsequent studies and may be an alternative to dermal fillers due to the expected lasting effects.

Eicosapentaenoic acid potentiates the therapeutic effects of adipose tissue-derived mesenchymal stromal cells on lung and distal organ injury in experimental sepsis.

BACKGROUND: Even though mesenchymal stromal cells (MSCs) mitigate lung and distal organ damage in experimental polymicrobial sepsis, mortality remains high. We investigated whether preconditioning with eicosapentaenoic acid (EPA) would potentiate MSC actions in experimental sepsis by further decreasing lung and distal organ injury, thereby improving survival. METHODS: In C57BL/6 mice, sepsis was induced by cecal hligation and puncture (CLP); sham-operated animals were used as control. Twenty-four hours after surgery, CLP mice were further randomized to receive saline, adipose tissue-derived (AD)-MSCs (105, nonpreconditioned), or AD-MSCs preconditioned with EPA for 6 h (105, EPA-preconditioned MSCs) intravenously. After 24 h, survival rate, sepsis severity score, lung mechanics and histology, protein level of selected biomarkers in lung tissue, cellularity in blood, distal organ damage, and MSC distribution (by technetium-99m tagging) were analyzed. Additionally, the effects of EPA on the secretion of resolvin-D1 (RvD1), prostaglandin E2 (PGE2), interleukin (IL)-10, and transforming growth factor (TGF)-ß1 by MSCs were evaluated in vitro. RESULTS: Nonpreconditioned and EPA-preconditioned AD-MSCs exhibited similar viability and differentiation capacity, accumulated mainly in the lungs and kidneys following systemic administration. Compared to nonpreconditioned AD-MSCs, EPA-preconditioned AD-MSCs further reduced static lung elastance, alveolar collapse, interstitial edema, alveolar septal inflammation, collagen fiber content, neutrophil cell count as well as protein levels of interleukin-1ß and keratinocyte chemoattractant in lung tissue, and morphological abnormalities in the heart (cardiac myocyte architecture), liver (hepatocyte disarrangement and Kupffer cell hyperplasia), kidney (acute tubular necrosis), spleen (increased number of megakaryocytes and lymphocytes), and small bowel (villi architecture disorganization). EPA preconditioning of MSCs resulted in increased secretion of pro-resolution and anti-inflammatory mediators (RvD1, PGE2, IL-10, and TGF-ß). CONCLUSIONS: Compared to nonpreconditioned cells, EPA-preconditioned AD-MSCs yielded further reductions in the lung and distal organ injury, resulting in greater improvement in sepsis severity score and higher survival rate in CLP-induced experimental sepsis. This may be a promising therapeutic approach to improve outcome in septic patients.

External jugular vein hemangioma: case report.

Hemangioma is a common tumor, normally diagnosed in children, and accounting for almost 10% of benign neoplasms. A hemangioma arising from the wall of a vessel is rare, and must be differentiated from other vascular malformations of the same origin. We report a rare case of a hemangioma arising from the wall of an external jugular vein and discuss diagnostic work-up and management.

Effects of Protective Mechanical Ventilation With Different PEEP Levels on Alveolar Damage and Inflammation in a Model of Open Abdominal Surgery: A Randomized Study in Obese Versus Non-obese Rats.

Intraoperative positive end-expiratory pressure (PEEP) has been proposed to restore lung volumes and improve respiratory function in obesity. However, the biological impact of different PEEP levels on the lungs in obesity remains unknown. We aimed to compare the effects of PEEP = 2 cmH2O versus PEEP = 6 cmH2O during ventilation with low tidal volumes on lung function, histology, and biological markers in obese and non-obese rats undergoing open abdominal surgery. Forty-two Wistar rats (21 obese, 21 non-obese) were anesthetized and tracheotomized, and laparotomy was performed with standardized bowel manipulation. Rats were randomly ventilated with protective tidal volume (7 ml/kg) at PEEP = 2 cmH2O or PEEP = 6 cmH2O for 4 h, after which they were euthanized. Lung mechanics and histology, alveolar epithelial cell integrity, and biological markers associated with pulmonary inflammation, alveolar stretch, extracellular matrix, and epithelial and endothelial cell damage were analyzed. In obese rats, PEEP = 6 cmH2O compared with PEEP = 2 cmH2O was associated with less alveolar collapse (p = 0.02). E-cadherin expression was not different between the two PEEP groups. Gene expressions of interleukin (IL)-6 (p = 0.01) and type III procollagen (p = 0.004), as well as protein levels of tumor necrosis factor-alpha (p = 0.016), were lower at PEEP = 6 cmH2O than at PEEP = 2 cmH2O. In non-obese animals, PEEP = 6 cmH2O compared with PEEP = 2 cmH2O led to increased hyperinflation, reduced e-cadherin (p = 0.04), and increased gene expression of IL-6 (p = 0.004) and protein levels of tumor necrosis factor-alpha (p-0.029), but no changes in fibrogenesis. In conclusion, PEEP = 6 cmH2O reduced lung damage and inflammation in an experimental model of mechanical ventilation for open abdominal surgery, but only in obese animals.