Amplifying the Effects of Contrast Agents on Magnetic Resonance Images Using a Deep Learning Method Trained on Synthetic Data.

OBJECTIVES: Artificial intelligence (AI) methods can be applied to enhance contrast in diagnostic images beyond that attainable with the standard doses of contrast agents (CAs) normally used in the clinic, thus potentially increasing diagnostic power and sensitivity. Deep learning-based AI relies on training data sets, which should be sufficiently large and diverse to effectively adjust network parameters, avoid biases, and enable generalization of the outcome. However, large sets of diagnostic images acquired at doses of CA outside the standard-of-care are not commonly available. Here, we propose a method to generate synthetic data sets to train an "AI agent" designed to amplify the effects of CAs in magnetic resonance (MR) images. The method was fine-tuned and validated in a preclinical study in a murine model of brain glioma, and extended to a large, retrospective clinical human data set. MATERIALS AND METHODS: A physical model was applied to simulate different levels of MR contrast from a gadolinium-based CA. The simulated data were used to train a neural network that predicts image contrast at higher doses. A preclinical MR study at multiple CA doses in a rat model of glioma was performed to tune model parameters and to assess fidelity of the virtual contrast images against ground-truth MR and histological data. Two different scanners (3 T and 7 T, respectively) were used to assess the effects of field strength. The approach was then applied to a retrospective clinical study comprising 1990 examinations in patients affected by a variety of brain diseases, including glioma, multiple sclerosis, and metastatic cancer. Images were evaluated in terms of contrast-to-noise ratio and lesion-to-brain ratio, and qualitative scores. RESULTS: In the preclinical study, virtual double-dose images showed high degrees of similarity to experimental double-dose images for both peak signal-to-noise ratio and structural similarity index (29.49 dB and 0.914 dB at 7 T, respectively, and 31.32 dB and 0.942 dB at 3 T) and significant improvement over standard contrast dose (ie, 0.1 mmol Gd/kg) images at both field strengths. In the clinical study, contrast-to-noise ratio and lesion-to-brain ratio increased by an average 155% and 34% in virtual contrast images compared with standard-dose images. Blind scoring of AI-enhanced images by 2 neuroradiologists showed significantly better sensitivity to small brain lesions compared with standard-dose images (4.46/5 vs 3.51/5). CONCLUSIONS: Synthetic data generated by a physical model of contrast enhancement provided effective training for a deep learning model for contrast amplification. Contrast above that attainable at standard doses of gadolinium-based CA can be generated through this approach, with significant advantages in the detection of small low-enhancing brain lesions.

Fine needle aspiration cytology of a myxoid adrenocortical adenoma. A case report.

The myxoid variant of adrenocortical (AC) tumors is characterized by peculiar histologic features that differ from conventional ones. It shows a prominent myxoid stromal component and is composed of small cells with mild atypia arranged in cords, pseudoglandular structures and microcysts. Reflecting the rarity of this variant, very few cytologic descriptions are available. We describe one case in a 41-year-old woman with a previous diagnosis of breast carcinoma and BRCA1 mutation. During follow-up controls, an adrenal tumor was discovered. Fine needle aspiration cytology and Tru-Cut biopsies were performed simultaneously. Smears showed numerous groups of cohesive cells of intermediate to small size. Within the largest groups, aggregates of myxoid metachromatic material were evident. This myxoid material could also be observed as isolated acellular fragments. While the cytoplasm of most tumoral cells was homogenously stained some showed small vacuoles. Histologically, the tumor grew, forming anastomosing cords, separated by myxoid material that determined microcystic spaces. Immunohistochemistry was characteristic of AC myxoid tumor. After surgery, pathologic analysis confirmed this diagnosis. The tumor showed no necrosis or invasion, had a low mitotic index (3/50 high power fields) and Ki-67 proliferative index of 15%. According to the different diagnostic systems the tumor was classified as an adenoma. In conclusion, the myxoid variant of AC tumors shows peculiar cytologic features. If unaware of the existence of this variant, it can easily be misinterpreted as a metastatic tumor.

An ultrasound-guided injection method for a syngeneic orthotopic murine model of breast cancer.

Breast cancer is the most common cancer among women worldwide. For high-risk women, contrast enhanced (CE)-magnetic resonance imaging (MRI) is recommended as supplemental screening together with mammography. The development of new MRI contrast agents is an active field of research, which requires efficacy tests on appropriate preclinical pathological models. In this work, a refined method to orthotopically induce breast cancer in BALB/c mice was developed using ultrasound (US) as a guide for the precise localisation of the tumour induction site and to improve animal welfare. The method was coupled with CE-MRI to characterise the evolution of the tumoural lesion.

Macrocyclic MR contrast agents: evaluation of multiple-organ gadolinium retention in healthy rats.

OBJECTIVES: The purpose of this study was to compare Gd levels in rat tissues after cumulative exposure to four commercially available macrocyclic gadolinium-based contrast agents (GBCAs). METHODS: Sixty-five male Sprague-Dawley rats were randomized to four exposure groups (n = 15 per group) and one control group (n = 5). Animals in each exposure group received 20 GBCA administrations (four per week of ProHance®, Dotarem®, Clariscan™, or Gadovist® for 5 consecutive weeks) at a dose of 0.6 mmol/kg bodyweight. After 28-days' recovery, animals were sacrificed and tissues harvested for Gd determination by inductively coupled plasma-mass spectroscopy (ICP-MS). Histologic assessment of the kidney tissue was performed for all animals. RESULTS: Significantly (p ≤ 0.005; all evaluations) lower Gd levels were noted with ProHance® than with Dotarem®, Clariscan™, or Gadovist® in all soft tissue organs: 0.144 ± 0.015 nmol/g vs. 0.342 ± 0.045, 0.377 ± 0.042, and 0.292 ± 0.047 nmol/g, respectively, for cerebrum; 0.151 ± 0.039 nmol/g vs. 0.315 ± 0.04, 0.345 ± 0.053, and 0.316 ± 0.040 nmol/g, respectively, for cerebellum; 0.361 ± 0.106 nmol/g vs. 0.685 ± 0.330, 0.823 ± 0.495, and 1.224 ± 0.664 nmol/g, respectively, for liver; 38.6 ± 25.0 nmol/g vs. 172 ± 134, 212 ± 121, and 294 ± 127 nmol/g, respectively, for kidney; and 0.400 ± 0.112 nmol/g vs. 0.660 ± 0.202, 0.688 ± 0.215, and 0.999 ± 0.442 nmol/g, respectively, for skin. No GBCA-induced macroscopic or microscopic findings were noted in the kidneys. CONCLUSIONS: Less Gd is retained in the brain and body tissues of rats 28 days after the last exposure to ProHance® compared to other macrocyclic GBCAs, likely due to unique physico-chemical features that facilitate more rapid and efficient clearance.

Orthotopic induction of CH157MN convexity and skull base meningiomas into nude mice using stereotactic surgery and MRI characterization.

Meningioma in vivo research is hampered by the difficulty of establishing an easy and reproducible orthotopic model able to mimic the characteristics of a human meningioma. Moreover, leptomeningeal dissemination and high mortality are often associated with such orthotopical models, making them useless for clinical translation studies. An optimized method for inducing meningiomas in nude mice at two different sites is described in this paper and the high reproducibility and low mortality of the models are demonstrated. Skull base meningiomas were induced in the auditory meatus and convexity meningiomas were induced on the brain surface of 23 and 24 nude mice, respectively. Both models led to the development of a mass easily observable by imaging methods. Dynamic contrast enhanced MRI was used as a tool to monitor and characterize the pathology onset and progression. At the end of the study, histology was performed to confirm the neoplastic origin of the diseased mass.

Exploring the intramolecular catalysis of the proton exchange process to modulate the relaxivity of Gd(iii)-complexes of HP-DO3A-like ligands.

The Gd(iii)-complexes of three novel HP-DO3A-like ligands have been investigated to assess the relationship between relaxometry and intramolecular catalysis of the proton exchange. The structures of these ligands differ from the parent HP-DO3A because the methyl group of the hydroxy-propyl arm has been replaced by -Ph-OH, -Ph-NH2 and -Ph-COOH, respectively. The phenol, amine and carboxylate functionalities display an intramolecular H-bonding with the coordinated hydroxyl moiety that affects either the pK values of the involved functionalities and the rate of the proton exchange process.

Exploiting the Proton Exchange as an Additional Route to Enhance the Relaxivity of Paramagnetic MRI Contrast Agents.

The relaxivity of Gd(HP-DO3A) was studied as a function of pH and buffer composition in order to identify the main factors of the observed relaxation enhancement due to the exchange of the coordinated hydroxyl proton. It was established that the paramagnetic relaxation time, T1M, of the coordinated hydroxyl proton is about 50% shorter than that of the protons in the coordinated water molecule. The control of the p K of the coordinated alcoholic -OH moiety in the ligand is fundamental to utilize the proton exchange enhanced relaxivity under physio/pathologic conditions. A new derivative of Gd(HP-DO3A) was synthesized by replacing the -CH3 group with a -CF3 moiety. In this complex, the -OH group becomes more acidic. Consequently, the maximum contribution of the proton exchange to the relaxivity is shifted to a lower pH region with the fluorinated ligand.

Synthesis, Characterization, and Biodistribution of a Dinuclear Gadolinium Complex with Improved Properties as a Blood Pool MRI Agent.

A dinuclear gadolinium(III) chelate containing two moieties of diethylenetriaminepentaacetic acid (DTPA), covalently conjugated to an analogue of deoxycholic acid, was synthesized and thoroughly characterized. A full relaxometric analysis was carried out, consisting of 1) the acquisition of nuclear magnetic resonance dispersion (NMRD) profiles in various media; 2) the study of binding affinity to serum albumin; 3) the measurement of 17 O transverse relaxation rate versus temperature, and 4) a transmetallation assay. In vivo biodistribution MRI studies at 1 T and blood pharmacokinetics assays were carried out in comparison with Gd-DTPA (Magnevist) and gadocoletic acid trisodium salt (B22956/1), two well-known Gd complexes that share the same chelating cage and the same deoxycholic acid residue of the Gd complex investigated herein ((GdDTPA)2 -Chol). High affinity for plasma protein and, in particular, the availability of more than one binding site, allows the complex to reach a fairly high relaxivity value in plasma (∼20 mm-1 s-1 , 20 MHz, 310 K) as well as to show unexpectedly enhanced properties of blood pooling, with an elimination half-life in rats approximately seven times longer than that of B22956/1.

Macrocyclic paramagnetic agents for MRI: Determinants of relaxivity and strategies for their improvement.

PURPOSE: To dissect the contributions to the longitudinal relaxivity (r1 ) of two commercial contrast agents (CAs), Gd-DOTA and Gd-HP-DO3A, and to synthesize/characterize a novel macrocyclic agent (Gd-Phen-DO3A) having superior r1 . METHODS: Longitudinal relaxation rates R1 of the CAs in saline with/without human serum albumin (HSA), ionized simulated body fluid (i-SBF), viscous simulated body fluid (v-SBF), and human plasma were measured. Results have been interpreted to evince the main determinants to the observed r1 values. RESULTS: In v-SBF or in the presence of HSA, r1 is enhanced for all complexes, reflecting the viscosity increase and a weak interaction with proteins. The CAs further differentiate in plasma, with a relaxivity increase (versus saline) of approximately 1, 1.5, and 2.5 mM-1 s-1 for Gd-DOTA, Gd-HPDO3A, and Gd-Phen-DO3A, respectively. R1 versus pH curves in i-SBF indicates that prototropic exchange sizably contributes to the relaxivity of Gd-HP-DO3A and Gd-Phen-DO3A. CONCLUSION: The major contributions to r1 in the physiological environment have been highlighted, namely, increased viscosity, complex-protein interaction, and prototropic exchange. The control of these terms allows the design of novel macrocyclic structures with enhanced r1 as a result of an improved interaction with plasma's macromolecules and the shift of the prototropic exchange to physiological pH. Magn Reson Med 78:1523-1532, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Ultraflex precision colonic stent placement as a bridge to surgery in patients with malignant colon obstruction.

BACKGROUND: Emergency surgery for malignant colon obstruction entails relatively high morbidity and mortality rates and typically necessitates a 2-step resection. These problems might be potentially mitigated by placement of a self-expanding metal stent (SEMS) as a bridge to surgery. A nitinol colorectal SEMS may offer several advantages, but available evidence on the utility of this SEMS type remains highly limited. OBJECTIVE: Our purpose was to evaluate the effectiveness and safety as a bridge to surgery of a nitinol SEMS designed for colorectal use. DESIGN: Prospective and retrospective multicenter clinical study. SETTING: Sixteen European study centers. PATIENTS: Thirty-six patients with malignant colonic obstruction. INTERVENTIONS: Nitinol colorectal SEMS placement. MAIN OUTCOME MEASURES: Technical success in accurate SEMS placement with coverage of the entire stricture length, clinical success in alleviating colonic obstructive symptoms, and bridging to elective surgery. RESULTS: Technical success was achieved in 97% of patients with a 95% CI of 85% to 100% and clinical success in 81% (95% CI, 64%-92%). Elective surgery was performed in 94% (95% CI, 81%-99%) of patients at a median of 11 days (95% CI, 7-15 days) after SEMS placement. SEMS-related perforation occurred in 3 patients. LIMITATIONS: No control group was included in this nonrandomized cohort study. CONCLUSIONS: In this first comparatively large clinical study of a nitinol colorectal SEMS as a bridge to surgery, a high proportion of patients successfully proceeded to elective surgery after prior decompression by SEMS placement.

[Upper digestive hemorrhage due to aortoesophageal fistula]. / Hemorragia digestiva alta por fístula aortoesofágica.

We describe the case of a 60-year-old woman who presented with thoracic pain followed by hematemesis. Aortoesophageal fistula was diagnosed. Double aortic and esophageal protheses were placed with good clinical outcome. After 15 days, the patient presented migration of the esophageal prothesis and a further endoscopic examination was performed. A fishbone was visualized in the fistula orifice.

Hemorragia digestiva alta por fístula aortoesofágica / Upper digestive hemorrhage due to aortoesophageal fistula

Se describe el caso clínico de una mujer de 60 años de edad, que comenzó con dolor torácico y un posterior episodio de hematemesis. Se diagnosticó una fístula aortoesofágica, por lo que se colocó una doble prótesis aórtica y esofágica, con buena evolución clínica. A los 15 días presentó migración de la prótesis esofágica y se realizó una nueva endoscopia, que permitió visualizar una espina de pescado enclavada en el esófago

We describe the case of a 60-year-old woman who presented with thoracic pain followed by hematemesis. Aortoesophageal fistula was diagnosed. Double aortic and esophageal protheses were placed with good clinical outcome. After 15 days, the patient presented migration of the esophageal prothesis and a further endoscopic examination was performed. A fishbone was visualized in the fistula orifice

[Life-threatening hemoptysis in cystic fibrosis: clinical characteristics and management in 36 episodes]. / Hemoptisis amenazante en la fibrosis quística: descripción clínica y actitud terapéutica en 36 episodios.

BACKGROUND: Our goal was to evaluate the clinical characteristics and management of life-threatening hemoptysis in patients with cystic fibrosis (CF). PATIENTS AND METHOD: We included adult CF patients followed up at the Cystic Fibrosis Units of the Autonomous Community of Madrid who had life-threatening hemoptysis from June 1990 to December 1999. RESULTS: Twelve CF patients (4 females) developed 36 episodes of life-threatening hemoptysis (30 massive and 6 recurrent). Lung disease was moderate to severe. Sputum cultures revealed Pseudomonas aeruginosa in 10 patients. Thirteen episodes (36%) resolved upon antibiotic treatment and 3 (8%) after antibiotic therapy and bronchoscopy. Bronchial artery embolization (BAE) was performed in 20 of 36 events. Immediate technique success was achieved in 80% episodes (16 of 20) after one session, 85% (17/20) after two sessions, and 95% (19/20) after three sessions. No major complications associated with the procedure were seen. The overall recurrence rate per episode was 69% (24 of 35 episodes in 6 patients) with a mean time of recurrence of 13 months. There were no massive hemoptysis-associated deaths during the follow-up. CONCLUSIONS: Life-threatening hemoptysis is a frequent complication in CF patients who have moderate or severe lung disease. When conservative therapeutic measures (including antibiotics) fail to control it, BAE should be performed. When performed by expert professionals, BAE is effective and safe to immediate control of life-threatening hemoptysis in patients with CF.

Hemoptisis amenazante en la fibrosis quística: descripción clínica y actitud terapéutica en 36 episodios / Life-threatening hemoptysis in cystic fibrosis: clinical characteristics and management in 36 episodes

FUNDAMENTO: El objetivo del trabajo es valorar la eficacia de la reacción en cadena de la polimerasa (PCR) anidada para el diagnóstico de laboratorio de la infección toxoplásmica activa en pacientes con infección por el virus de la inmunodeficiencia humana (VIH). PACIENTES Y MÉTODO: Se realizó un estudio en 157 pacientes con infección por el VIH en quienes se investigó la presencia de anticuerpos anti Toxoplasma gondii IgG, IgM e IgA, así como de ADN de T. gondii mediante PCR anidada en muestras de sangre periférica. RESULTADOS: El estudio demostró la presencia de ADN del parásito en 11 pacientes, anticuerpos IgG anti-T. gondii en 56, del tipo IgM en uno y del tipo IgA en 5. CONCLUSIONES: La técnica de PCR anidada es una herramienta rápida, sensible y eficaz en el diagnóstico temprano de toxoplasmosis en pacientes con infección por el VIH, además de ser útil para la indicación del tratamiento en individuos asintomáticos FUNDAMENTO: Estudiar la presentación clínica y actitud terapéutica ante la hemoptisis amenazante en los pacientes con fibrosis quística (FQ).PACIENTES Y MÉTODO: Pacientes con FQ mayores de 18 años atendidos en la Comunidad Autónoma de Madrid que presentaron hemoptisis amenazante entre enero de 1990 y diciembre de 1999.RESULTADOS: Doce pacientes (4 mujeres y 8 varones) con FQ presentaron 36 episodios de hemoptisis amenazante. En 30 casos fue masiva y en 6 recurrente. La afección pulmonar era moderada-grave. Diez pacientes tenían colonización pulmonar por Pseudomonas aeruginosa. De los 36 episodios de hemoptisis, 13 (36 por ciento) se solucionaron con tratamiento antibiótico y tres (8 por ciento) con tratamiento antibiótico y fibrobroncoscopia. En los 20 episodios restantes se realizó embolización de las arterias bronquiales. La eficacia de la embolización para el control de la hemoptisis fue de un 80 por ciento (16 de 20 episodios) con una sesión de embolización, de un 85 por ciento (17/20) con dos sesiones y de un 95 por ciento (19/20) con tres sesiones. No hubo ninguna complicación mayor por la embolización. La tasa de recurrencia por episodio fue de un 69 por ciento (24/35 episodios, en 6 pacientes), con un tiempo medio de recurrencia de 13 meses. Durante el seguimiento no se produjeron muertes secundarias a la hemoptisis. CONCLUSIONES: La hemoptisis amenazante es frecuente en los pacientes con FQ y afección pulmonar moderada-grave. Si la hemorragia no cesa con tratamiento conservador (incluyendo antibióticos), debe realizarse embolización de las arterias bronquiales. Esta técnica es efectiva y segura cuando la lleva a cabo personal experto (AU)