Combining machine learning and texture analysis to differentiate mediastinal lymph nodes in lung cancer patients.

Evaluate whether texture analysis associated with machine learning approaches could differentiate between malignant and benign lymph nodes. A total 18 patients with lung cancer were selected, with 39 lymph nodes, being 15 malignant and 24 benign. Retrospective computed tomography scans were utilized both with and without contrast medium. The great differential of this work was the use of 15 textures from mediastinal lymph nodes, with five different physicians as operators. First and second order statistical textures such as gray level run length and co-occurrence matrix were extracted and applied to three different machine learning classifiers. The best machine learning classifier demonstrated a variability of less than 5% among operators. The support vector machine (SVM) classifier presented 95% of the area under the ROC curve (AUC) and 89% of sensitivity for sequences without contrast medium. SVM classifier presented 93% of AUC and 86% of sensitivity for sequences with contrast medium. Texture analysis and machine learning may be helpful in the differentiation between malign and benign lymph nodes. This study can aid the physician in diagnosis and staging of lymph nodes and potentially reduce the number of invasive analysis to histopathological confirmation.

Predictive Model for Delivery Efficiency: Erythrocyte Membrane-Camouflaged Magnetofluorescent Nanocarriers Study.

Delivery efficiencies of theranostic nanoparticles (NPs) based on passive tumor targeting strongly depend either on their blood circulation time or on appropriate modulations of the tumor microenvironment. Therefore, predicting the NP delivery efficiency before and after a tumor microenvironment modulation is highly desirable. Here, we present a new erythrocyte membrane-camouflaged magnetofluorescent nanocarrier (MMFn) with long blood circulation time (92 h) and high delivery efficiency (10% ID for Ehrlich murine tumor model). MMFns owe their magnetic and fluorescent properties to the incorporation of manganese ferrite nanoparticles (MnFe2O4 NPs) and IR-780 (a lipophilic indocyanine fluorescent dye), respectively, to their erythrocyte membrane-derived camouflage. MMFn composition, morphology, and size, as well as optical absorption, zeta potential, and fluorescent, magnetic, and magnetothermal properties, are thoroughly examined in vitro. We then present an analytical pharmacokinetic (PK) model capable of predicting the delivery efficiency (DE) and the time of peak tumor uptake (tmax), as well as changes in DE and tmax due to modulations of the tumor microenvironment, for potentially any nanocarrier. Experimental PK data sets (blood and tumor amounts of MMFns) are simultaneously fit to the model equations using the PK modeling software Monolix. We then validate our model analytical solutions with the numerical solutions provided by Monolix. We also demonstrate how our a priori nonmechanistic model for passive targeting relates to a previously reported mechanistic model for active targeting. All in vivo PK studies, as well as in vivo and ex vivo biodistribution studies, were conducted using two noninvasive techniques, namely, fluorescence molecular tomography (FMT) and alternating current biosusceptometry (ACB). Finally, histopathology corroborates our PK and biodistribution results.

Influence of post-transplant immunosuppressive therapy on gastrointestinal transit using biomagnetic method: a pilot study.

BACKGROUND: Immunosuppressive therapy after kidney transplant is necessary to prevent allograft rejection and it is the cause of several gastrointestinal (GI) disorders that have been scantily studied. OBJECTIVES: This study was aimed at investigating the influence of triple immunosuppressive therapy on GI transit in renal transplant patients by employing a biomagnetic technique. METHODS: Twenty-one renal transplant patients underwent triple therapy, which included either tacrolimus (TAC) or cyclosporin A (CsA) associated with prednisone and azathioprine. They were all evaluated, and fifteen other healthy individuals formed the control group. After a standardized meal, GI transit of magnetic markers was assessed using Alternating Current Biosusceptometry (ACB). RESULTS: Patients taking TAC had significantly accelerated gastric emptying and colonic arrival (p ≤ 0.001) when compared with those taking CsA and those in the control group. However, no differences were observed in small bowel transit among the groups studied. Overall, the inter-subject coefficients of variation for gastrointestinal transit parameters were higher for the TAC group and similar for the CsA and control groups. CONCLUSION: This study demonstrated that ACB is a suitable methodology when evaluating the influence of different immunosuppressive therapies on gastrointestinal transit after renal transplantation. Pronounced inter-individual variation was found in patients treated with tacrolimus, thus showing the prokinetic effect of this drug on GI motility. Studies of motility patterns in this population could be useful as complementary information toward determining the mechanisms and the relationship between motility and therapeutic doses.

Different patterns between mechanical and electrical activities: an approach to investigate gastric motility in a model of long-term diabetic rats.

The relationship between time-courses of mechanical and electrical events in longstanding diabetes was investigated in rats. Magnetic markers and electrodes were surgically implanted in the gastric serosa of male rats. Simultaneous recordings were obtained by AC biosusceptometry, electromyography and electrogastrography one, three and six months after injections of saline (control) or alloxan (diabetic). Frequency and amplitude of contraction, abnormal rhythmic index and half-bandwidth were obtained (ANOVA P < 0.05). Antral hypomotility and gastric motility instability were observed in the signal waveform of diabetic rats at the three time points of study. The mean frequency (4.4 ± 0.4 cpm) was strictly similar, but the mechanical and electrical correlation was lowest for diabetics groups. Decreases in mechanical amplitude were observed for all diabetic groups compared with control; also the ranges of frequency were much wider in diabetes. The half-bandwidth increased since the first month in mechanical recordings and only after the third month in electrical. In diabetic animals, about 40% of gastric activity was abnormal (against 12% in control) and may reach 60% in the sixth month of mechanical recordings. The multi-instrumental approach showed a more substantial deterioration in mechanical activity and created an integrative view of gastric motility for longstanding diabetic model.

Development of an AMR-ACB array for gastrointestinal motility studies.

The association between anisotropic magnetoresistive (AMR) sensor and AC biosusceptometry (ACB) to evaluate gastrointestinal motility is presented. The AMR-ACB system was successfully characterized in a bench-top study, and in vivo results were compared with those obtained by means of simultaneous manometry. Both AMR-ACB and manometry techniques presented high temporal cross correlation between the two periodicals signals . The contraction frequencies using AMR-ACB were 73.9 ± 7.6 mHz and using manometry were 73.8 ± 7.9 mHz during the baseline . The amplitude of contraction using AMR-ACB was 396 ± 108 µT·s and using manometry were 540 ± 198 mmHg·s during the baseline. The amplitudes of signals for AMR-ACB and manometric recordings were similarly increased to 86.4% and 89.3% by neostigmine, and also decreased to 27.2% and 21.4% by hyoscine butylbromide in all animals, respectively. The AMR-ACB array is nonexpensive, portable, and has high-spatiotemporal resolution to provide helpful information about gastrointestinal tract.

Employment of a noninvasive magnetic method for evaluation of gastrointestinal transit in rats.

AC Biosusceptometry (ACB) was previously employed towards recording gastrointestinal motility. Our data show a reliable and successful evaluation of gastrointestinal transit of liquid and solid meals in rats, considering the methods scarcity and number of experiments needed to endorsement of drugs and medicinal plants. ACB permits real time and simultaneous experiments using the same animal, preserving the physiological conditions employing both meals with simplicity and accuracy.

Effects of meal size and proximal-distal segmentation on gastric activity.

AIM: To evaluate the effects of meal size and three segmentations on intragastric distribution of the meal and gastric motility, by scintigraphy. METHODS: Twelve healthy volunteers were randomly assessed, twice, by scintigraphy. The test meal consisted of 60 or 180 mL of yogurt labeled with 64 MBq (99m)Tc-tin colloid. Anterior and posterior dynamic frames were simultaneously acquired for 18 min and all data were analyzed in MatLab. Three proximal-distal segmentations using regions of interest were adopted for both meals. RESULTS: Intragastric distribution of the meal between the proximal and distal compartments was strongly influenced by the way in which the stomach was divided, showing greater proximal retention after the 180 mL. An important finding was that both dominant frequencies (1 and 3 cpm) were simultaneously recorded in the proximal and distal stomach; however, the power ratio of those dominant frequencies varied in agreement with the segmentation adopted and was independent of the meal size. CONCLUSION: It was possible to simultaneously evaluate the static intragastric distribution and phasic contractility from the same recording using our scintigraphic approach.

AC Biosusceptometry as a method for measuring gastric contraction.

The aim of this study was to validate the alternate current biosusceptometry (ACB) for monitoring gastric contractions in rats. In vitro data were obtained to establish the relationship between ACB and the strain-gauge (SG) signal amplitude. In vivo experiments were performed on rats with magnetic markers and SGs previously implanted under the gastric serosa. The effects of the prandial state in gastric motility profiles were obtained. The correlation between in vitro signal amplitudes was strong (R = 0.989). The temporal cross-correlation between the ACB and SG signal amplitude was higher in the postprandial than in the fasting state. Irregular signal profiles, low contraction amplitudes, and smaller signal-to-noise ratios explained the poor correlation for fasting-state recordings. The contraction frequencies using ACB were 0.068 ± 0.007 Hz (postprandial) and 0.058 ± 0.007 Hz (fasting) and those using SG were 0.066 ± 0.006 Hz (postprandial) and 0.059 ± 0.008 Hz (fasting) (P < 0.003). When a magnetic tracer was ingested, there was a strong correlation and a small phase-difference between techniques. We conclude that ACB provides an accurate and sensitive technique for studies of GI motility in the rat.

The ACB technique: a biomagentic tool for monitoring gastrointestinal contraction directly from smooth muscle in dogs.

The aim of this paper was to verify whether AC biosusceptometry (ACB) is suitable for monitoring gastrointestinal (GI) contraction directly from smooth muscle in dogs, comparing with electrical recordings simultaneously. All experiments were performed in dogs with magnetic markers implanted under the serosa of the right colon and distal stomach, and their movements were recorded by ACB. Monopolar electrodes were implanted close to the magnetic markers and their electric potentials were recorded by electromyography (EMG). The effects of neostigmine, hyoscine butylbromide and meal on gastric and colonic parameters were studied. The ACB signal from the distal stomach was very similar to EMG; in the colonic recordings, however, within the same low-frequency band, ACB and EMG signals were characterized by simultaneity or a widely changeable frequency profile with time. ACB recordings were capable of demonstrating the changes in gastric and colonic motility determined by pharmacological interventions as well as by feeding. Our results reinforce the importance of evaluating the mechanical and electrical components of motility and show a temporal association between them. ACB and EMG are complementary for studying motility, with special emphasis on the colon. ACB offers an accurate method for monitoring in vivo GI motility.

Pharmaceutical applications of AC biosusceptometry.

AC Biosusceptometry offers an alternative to investigate noninvasively and without ionizing radiation the behavior of solid dosage forms in vitro and in the human gastrointestinal tract. This versatility allowed applying this technique in a wide field ranging from characterization of the disintegration process to elucidation of how the physiological parameters can interfere with pharmaceutical processes. It is increasingly important to understand how oral solid dosage forms behave in the human gastrointestinal tract. Once labelled, magnetic dosage forms provide an excellent opportunity to investigate complexes' interactions between dosage form and gastrointestinal physiology. In this paper, basic principles of this biomagnetic instrumentation and of the quantification based on magnetic images are reviewed. Also will be presented are some of the most recent applications of AC Biosusceptometry in the pharmaceutical research including oesophageal transit, gastric emptying and transit time of multiparticulate dosage forms, hydrophilic matrices and disintegration of tablets.

AC biosusceptometry technique to evaluate the gastrointestinal transit of pellets under influence of prandial state.

Multiparticulate dosage forms have been proposed when distal regions of gastrointestinal tract are desirable as target of drugs. It is known that physiological parameters might interfere with the processes related to the drug delivery and absorption and therefore, it is essential to evaluate the behavior of such delivery systems in vivo. The aim of this study was to propose the AC Biosusceptometry technique as a noninvasive and radiation free device to evaluate the gastrointestinal transit of a magnetic multiparticulate dosage form in healthy volunteers under fasting and fed conditions. Magnetic pellets were prepared by the powder layering method of ferrite on nonpareils sugar beads and coated by using Eudragit. Our data showed that the AC Biosusceptometry technique was able to monitoring the gastrointestinal transit of pellets presenting similar profiles as demonstrated by standard techniques. Food intake has markedly influenced the gastric emptying as well as the colon arrival and the small intestine transit of magnetic pellets.

Electrical and mechanical effects of hyoscine butylbromide on the human stomach: a non-invasive approach.

Due to the importance of motility in a number of gastrointestinal disorders, efforts have been made to evaluate both gastric motility counterparts: electrical activity and mechanical activity. The present work aimed to propose a new approach, associating AC biosusceptometry (ACB) and electrogastrography (EGG), to noninvasively monitoring mechanical and electrical gastric activity, respectively. Fourteen volunteers ingested a test meal and their gastric activity was evaluated by EGG and ACB at a baseline and after 20 mg of i.v. hyoscine butylbromide. ACB and EGG showed a similar signal pattern and high temporal correlation. Hyoscine butylbromide decreased the mechanical motility index (MI) by 50.9%, while for electrical MI the reduction was 36.5%. Delayed times to onset (mean+/-SD: 50+/-15 versus 40+/-20 s; P<0.01) and the inhibitory effect (16+/-4 versus 14+/-5 min; P<0.01) were calculated for ACB and EGG, respectively. ACB and EGG emerged due to their interesting nature, noninvasiveness and low cost to evaluate gastric motility. Our approach associating ACB and EGG allowed monitoring and quantification of the effects of an anticholinergic drug in gastric electrical activity and contractile activity in humans.

Gastric motility evaluated by electrogastrography and alternating current biosusceptometry in dogs.

Association techniques could be the answer for evaluating electromechanical coupling and gastric emptying under basal conditions and after administration of drugs. Electrogastrography (EGG) and alternating current biosusceptometry (ACB) emerged due to their interesting nature, noninvasiveness and low cost. The aims were to examine in dogs the effect of erythromycin on gastric emptying by ACB and electrical and motor responses to erythromycin and propranolol by ACB and EGG respectively. Twelve beagle dogs ingested a solid test meal on separate days. Under anesthesia, gastric motility was evaluated by EGG and ACB after erythromycin and propranolol administration. Without anesthesia, gastric emptying was assessed under basal conditions and after erythromycin by ACB. ACB and EGG showed a strong temporal correlation. Erythromycin and propranolol presented the same profile with different power ratios; the amplitude increased whereas frequency decreased. Also, erythromycin administration hastened gastric emptying while reducing the orocaecal transit time. There is a demand for reliable, easy-to-perform and comfortable techniques to record gastric emptying and gastric activity in medicine and veterinary practice. In summary, the association of ACB with EGG accompanied by an appropriate animal model is promising for evaluating effects of drugs in gastric myoelectrical and contractile activity.

Influence of compression forces on tablets disintegration by AC Biosusceptometry.

Analysis of physical phenomena that occurs during tablet disintegration has been studied by several experimental approaches; however none of them satisfactorily describe this process. The aim of this study was to investigate the influence of compression force on the tablets by associating the AC Biosusceptometry with consolidated methods in order to validate the biomagnetic technique as a tool for quality control in pharmaceutical processes. Tablets obtained at five compression levels were submitted to mechanical properties tests. For uncoated tablets, water uptake and disintegration force measurements were performed in order to compare with magnetic data. For coated tablets, magnetic measurements were carried out to establish a relationship between physical parameters of the disintegration process. According to the results, differences between the compression levels were found for water uptake, force development and magnetic area variation measurements. ACB method was able to estimate the disintegration properties as well as the kinetics of disintegration process for uncoated and coated tablets. This study provided a new approach for in vitro investigation and validated this biomagnetic technique as a tool for quality control for pharmaceutical industry. Moreover, using ACB will also be possible to test these parameters in humans allowing to establish an in vitro/in vivo correlation (IVIVC).

Enteric coated magnetic HPMC capsules evaluated in human gastrointestinal tract by AC biosusceptometry.

PURPOSE: To employ the AC Biosusceptometry (ACB) technique to evaluate in vitro and in vivo characteristics of enteric coated magnetic hydroxypropyl methylcellulose (HPMC) capsules and to image the disintegration process. MATERIALS AND METHODS: HPMC capsules filled with ferrite (MnFe2O4) and coated with Eudragit were evaluated using USP XXII method and administered to fasted volunteers. Single and multisensor ACB systems were used to characterize the gastrointestinal (GI) motility and to determine gastric residence time (GRT), small intestinal transit time (SITT) and orocaecal transit time (OCTT). Mean disintegration time (t50) was quantified from 50% increase of pixels in the imaging area. RESULTS: In vitro and in vivo performance of the magnetic HPMC capsules as well as the disintegration process were monitored using ACB systems. The mean disintegration time (t50) calculated for in vitro was 25+/-5 min and for in vivo was 13+/-5 min. In vivo also were determined mean values for GRT (55+/-19 min), SITT (185+/-82 min) and OCTT (240+/-88 min). CONCLUSIONS: AC Biosusceptometry is a non-invasive technique originally proposed to monitoring pharmaceutical dosage forms orally administered and to image the disintegration process.

Disintegration of magnetic tablets in human stomach evaluated by alternate current biosusceptometry.

Oral administration is the most convenient route for drug therapy. The knowledge of the gastrointestinal transit and specific site for drug delivery is a prerequisite for development of dosage forms. The aim of this work was to demonstrate that is possible to monitor the disintegration process of film-coated magnetic tablets by multi-sensor alternate current Biosusceptometry (ACB) in vivo and in vitro. This method is based on the recording of signals produced by the magnetic tablet using a seven sensors array and signal-processing techniques. The disintegration was confirmed by signals analysis in healthy human volunteers' measurements and in vitro experiments. Results showed that ACB is efficient to characterize the disintegration of dosage forms in the stomach, being a research tool for the development of new pharmaceutical dosage forms.