Amide proton transfer weighted imaging in pediatric neuro-oncology: initial experience.

Amide proton transfer weighted (APTw) imaging enables in vivo assessment of tissue-bound mobile proteins and peptides through the detection of chemical exchange saturation transfer. Promising applications of APTw imaging have been shown in adult brain tumors. As pediatric brain tumors differ from their adult counterparts, we investigate the radiological appearance of pediatric brain tumors on APTw imaging. APTw imaging was conducted at 3 T. APTw maps were calculated using magnetization transfer ratio asymmetry at 3.5 ppm. First, the repeatability of APTw imaging was assessed in a phantom and in five healthy volunteers by calculating the within-subject coefficient of variation (wCV). APTw images of pediatric brain tumor patients were analyzed retrospectively. APTw levels were compared between solid tumor tissue and normal-appearing white matter (NAWM) and between pediatric high-grade glioma (pHGG) and pediatric low-grade glioma (pLGG) using t-tests. APTw maps were repeatable in supratentorial and infratentorial brain regions (wCV ranged from 11% to 39%), except those from the pontine region (wCV between 39% and 50%). APTw images of 23 children with brain tumor were analyzed (mean age 12 years ± 5, 12 male). Significantly higher APTw values are present in tumor compared with NAWM for both pHGG and pLGG (p < 0.05). APTw values were higher in pLGG subtype pilocytic astrocytoma compared with other pLGG subtypes (p < 0.05). Non-invasive characterization of pediatric brain tumor biology with APTw imaging could aid the radiologist in clinical decision-making.

Performance of a Nonlinear Magnetic Handheld Probe for Intraoperative Sentinel Lymph Node Detection: A Phantom Study.

OBJECTIVE: This study investigates the performance of the DiffMag handheld probe (nonlinear magnetometry), to be used for sentinel lymph node detection. Furthermore, the performance of DiffMag is compared with a gamma probe and a first-order magnetometer (Sentimag®, linear magnetometry). METHODS: The performance of all three probes was evaluated based on longitudinal distance, transverse distance, and resolving power for two tracer volumes. A phantom was developed to investigate the performance of the probes for a clinically relevant situation in the floor of the mouth (FOM). RESULTS: Considering the longitudinal distance, both DiffMag handheld and Sentimag® probe had comparable performance, while the gamma probe was able to detect at least a factor of 10 deeper. Transverse distances of 13, 11, and 51 mm were measured for the small tracer volume by the DiffMag handheld, Sentimag®, and the gamma probe, respectively. For the large tracer volume this was 21, 18, and 55 mm, respectively. The full width at half maximum, at 7 mm probe height from the phantom surface, was 14, 12, and 18 mm for the small tracer volume and 15, 18, and 25 mm for the large tracer volume with the DiffMag handheld, Sentimag®, and gamma probe, respectively. CONCLUSIONS: With a high resolving power but limited longitudinal distance, the DiffMag handheld probe seems suitable for detecting SLNs which are in close proximity to the primary tumor. In this study, comparable results were shown using linear magnetometry. The gamma probe reached 10 times deeper, but has a lower resolving power compared with the DiffMag handheld probe.

Radiofrequency localization of nonpalpable breast cancer in a multicentre prospective cohort study: feasibility, clinical acceptability, and safety.

PURPOSE: In breast conserving surgery, accurate lesion localization is essential for obtaining adequate surgical margins. Preoperative wire localization (WL) and radioactive seed localization (RSL) are widely accepted methods to guide surgical excision of nonpalpable breast lesions but are limited by logistical challenges, migration issues, and legislative complexities. Radiofrequency identification (RFID) technology may offer a viable alternative. The purpose of this study was to evaluate the feasibility, clinical acceptability, and safety of RFID surgical guidance for localization of nonpalpable breast cancer. METHODS: In a prospective multicentre cohort study, the first 100 RFID localization procedures were included. The primary outcome was the percentage of clear resection margins and re-excision rate. Secondary outcomes included procedure details, user experience, learningcurve, and adverse events. RESULTS: Between April 2019 and May 2021, 100 women underwent RFID guided breast conserving surgery. Clear resection margins were obtained in 89 out of 96 included patients (92.7%), re-excision was indicated in three patients (3.1%). Radiologists reported difficulties with the placement of the RFID tag, partially related to the relatively large needle-applicator (12-gauge). This led to the premature termination of the study in the hospital using RSL as regular care. The radiologist experience was improved after a manufacturer modification of the needle-applicator. Surgical localization involved a low learning curve. Adverse events (n = 33) included dislocation of the marker during insertion (8%) and hematomas (9%). The majority of adverse events (85%) occurred using the first-generation needle-applicator. CONCLUSION: RFID technology is a potential alternative for non-radioactive and non-wire localization of nonpalpable breast lesions.

Near-Infrared Spectral Similarity between Ex Vivo Porcine and In Vivo Human Tissue.

BACKGROUND: In vivo diffuse reflectance spectroscopy provides additional contrast in discriminating nerves embedded in adipose tissue during surgery. However, large datasets are required to achieve clinically acceptable classification levels. This study assesses the spectral similarity between ex vivo porcine and in vivo human spectral data of nerve and adipose tissue, as porcine tissue could contribute to generate large datasets. METHODS: Porcine diffuse reflectance spectra were measured at 124 nerve and 151 adipose locations. A previously recorded dataset of 32 in vivo human nerve and 23 adipose tissue locations was used for comparison. In total, 36 features were extracted from the raw porcine to generate binary logistic regression models for all combinations of two, three, four and five features. Feature selection was performed by assessing similar means between normalized features of nerve and of adipose tissue (Kruskal-Wallis test, p < 0.05) and for models performing best on the porcine cross validation set. The human test set was used to assess classification performance. RESULTS: The binary logistic regression models with selected features showed an accuracy of 60% on the test set. CONCLUSIONS: Spectral similarity between ex vivo porcine and in vivo human adipose and nerve tissue was present, but further research is required.

A Comprehensive Grading System for a Magnetic Sentinel Lymph Node Biopsy Procedure in Head and Neck Cancer Patients.

A magnetic sentinel lymph node biopsy ((SLN)B) procedure has recently been shown feasible in oral cancer patients. However, a grading system is absent for proper identification and classification, and thus for clinical reporting. Based on data from eight complete magnetic SLNB procedures, we propose a provisional grading system. This grading system includes: (1) a qualitative five-point grading scale for MRI evaluation to describe iron uptake by LNs; (2) an ex vivo count of resected SLN with a magnetic probe to quantify iron amount; and (3) a qualitative five-point grading scale for histopathologic examination of excised magnetic SLNs. Most SLNs with iron uptake were identified and detected in level II. In this level, most variance in grading was seen for MRI and histopathology; MRI and medullar sinus were especially highly graded, and cortical sinus was mainly low graded. On average 82 ± 58 µg iron accumulated in harvested SLNs, and there were no significant differences in injected tracer dose (22.4 mg or 11.2 mg iron). In conclusion, a first step was taken in defining a comprehensive grading system to gain more insight into the lymphatic draining system during a magnetic SLNB procedure.

Breast MRI in patients after breast conserving surgery with sentinel node procedure using a superparamagnetic tracer.

BACKGROUND: A procedure for sentinel lymph node biopsy (SLNB) using superparamagnetic iron-oxide (SPIO) nanoparticles and intraoperative sentinel lymph node (SLN) detection was developed to overcome drawbacks associated with the current standard-of-care SLNB. However, residual SPIO nanoparticles can result in void artefacts at follow-up magnetic resonance imaging (MRI) scans. We present a grading protocol to quantitatively assess the severity of these artefacts and offer an option to minimise the impact of SPIO nanoparticles on diagnostic imaging. METHODS: Follow-up mammography and MRI of two patient groups after a magnetic SLNB were included in the study. They received a 2-mL subareolar dose of SPIO (high-dose, HD) or a 0.1-mL intratumoural dose of SPIO (low-dose, LD). Follow-up mammography and MRI after magnetic SLNB were acquired within 4 years after breast conserving surgery (BCS). Two radiologists with over 10-year experience in breast imaging assessed the images and analysed the void artefacts and their impact on diagnostic follow-up. RESULTS: A total of 19 patients were included (HD, n = 13; LD, n = 6). In the HD group, 9/13 patients displayed an artefact on T1-weighted images up to 3.6 years after the procedure, while no impact of the SPIO remnants was observed in the LD group. CONCLUSIONS: SLNB using a 2-mL subareolar dose of magnetic tracer in patients undergoing BCS resulted in residual artefacts in the breast in the majority of patients, which may hamper follow-up MRI. This can be avoided by using a 0.1-mL intratumoural dose.

Advancing intraoperative magnetic tracing using 3D freehand magnetic particle imaging.

PURPOSE: Sentinel lymph node biopsy is a routine procedure for nodal staging in penile cancer. Most commonly, this procedure is guided by radioactive tracers, providing various forms of preoperative and intraoperative guidance. This is further extended with fluorescence imaging using hybrid radioactive-fluorescence tracers. Alternatively, a magnetic-based approach has become available using superparamagnetic iron-oxide nanoparticles (SPIONs). This study investigates a novel freehand magnetic particle imaging and navigation modality (fhMPI) for intraoperative localization, along with a hybrid approach, combining magnetic and fluorescence guidance. MATERIALS AND METHODS: The fhMPI set-up was built with a surgical navigation device, optical tracking system and magnetometer probe. A dedicated reconstruction software based on a look-up-table method was used to reconstruct a superficial 3D volume of the SPION distribution in tissue. For fluorescence guidance, indocyanine green (ICG) was added to the SPIONs. The fhMPI modality was characterized in phantoms, ex vivo human skin and in vivo porcine surgery. RESULTS: Phantom and human skin explants illustrated that the current fhMPI modality had a sensitivity of 2.2 × 10-2 mg/mL SPIONs, a resolving power of at least 7 mm and a depth penetration up to 1.5 cm. Evaluation during porcine surgery showed that fhMPI allowed for an augmented reality image overlay of the tracer distribution in tissue, as well as 3D virtual navigation. Besides, using the hybrid approach, fluorescence imaging provided a visual confirmation of localized nodes. CONCLUSION: fhMPI is feasible in vivo, providing 3D imaging and navigation for magnetic nanoparticles in the operating room, expanding the guidance possibilities during magnetic sentinel lymph node procedures. Furthermore, the integration of ICG provides the ability to visually refine and confirm correct localization. Further clinical evaluation should verify these findings in human patients as well.

Laparoscopic Probe for Sentinel Lymph Node Harvesting Using Magnetic Nanoparticles.

OBJECTIVE: Sentinel lymph node harvesting is an essential step in the surgical treatment of a growing number of malignancies. Various techniques are available to facilitate this purpose. The present study reports a new laparoscopic technique for lymph node harvesting using magnetic nanoparticles containing a superparamagnetic iron-oxide core and dextran coating. This study assesses the clinical relevance of the prototype and provides input for further technological development on the way to clinical implementation. METHODS: A laparoscopic differential magnetometer prototype was built, utilizing a nonlinear detection principle (differential magnetometry) for magnetic identification of lymph nodes. The iron content sensitivity, depth & spatial sensitivity, and angular sensitivity were analyzed to investigate clinical options. RESULTS: The minimum detectable amount of iron was 9.8 µg at a distance of 1 mm. The detection depth was 5, 8, and 10 mm for samples containing 126, 252, and 504 µg iron, respectively. The maximum lateral detection distance was 5, 7, and 8 mm for samples containing 126, 252, and 504 µg iron, respectively. A sample containing 504 µg iron was detectable at all angulations assessed (0°, 30°, 60° and 90°). CONCLUSION: The laparoscopic differential magnetometer demonstrates promising results for further investigation and development towards laparoscopic lymph node harvesting using magnetic nanoparticles. SIGNIFICANCE: The laparoscopic differential magnetometer facilitates a novel method for sentinel lymph node harvesting, which helps to determine prognosis and treatment of cancer patients.

A complete magnetic sentinel lymph node biopsy procedure in oral cancer patients: A pilot study.

OBJECTIVES: To assess the feasibility and merits of a complete magnetic approach for a sentinel lymph node biopsy (SLNB) procedure in oral cancer patients. MATERIALS AND METHODS: This study included ten oral cancer patients (stage cT1-T2N0M0) scheduled for elective neck dissection (END). Superparamagnetic iron oxide nanoparticles (SPIO) were administered peritumorally prior to surgery. A preoperative MRI was acquired to identify lymph nodes (LNs) with iron uptake. A magnetic detector was used to identify magnetic hotspots prior, during, and after the SLNB procedure. The resected sentinel LNs (SLNs) were evaluated using step-serial sectioning, and the neck dissection specimen was assessed by routine histopathological examination. A postoperative MRI was acquired to observe any residual iron. RESULTS: Of ten primary tumors, eight were located in the tongue, one floor-of-mouth (FOM), and one tongue-FOM transition. SPIO injections were experienced as painful by nine patients, two of whom developed a tongue swelling. In eight patients, magnetic SLNs were successfully detected and excised during the magnetic SLNB procedure. During the END procedure, additional magnetic SLNs were identified in three patients. Histopathology confirmed iron deposits in sinuses of excised SLNs. Three SLNs were harboring metastases, of which one was identified only during the END procedure. The END specimens revealed no further metastases. CONCLUSION: A complete magnetic SLNB procedure was successfully performed in eight of ten patients (80% success rate), therefore the procedure seems feasible. Recommendations for further investigation are made including: use of anesthetics, magnetic tracer volume, planning preoperative MRI, comparison to conventional technique and follow-up.

New Developments in Imaging for Sentinel Lymph Node Biopsy in Early-Stage Oral Cavity Squamous Cell Carcinoma.

Sentinel lymph node biopsy (SLNB) is a diagnostic staging procedure that aims to identify the first draining lymph node(s) from the primary tumor, the sentinel lymph nodes (SLN), as their histopathological status reflects the histopathological status of the rest of the nodal basin. The routine SLNB procedure consists of peritumoral injections with a technetium-99m [99mTc]-labelled radiotracer followed by lymphoscintigraphy and SPECT-CT imaging. Based on these imaging results, the identified SLNs are marked for surgical extirpation and are subjected to histopathological assessment. The routine SLNB procedure has proven to reliably stage the clinically negative neck in early-stage oral squamous cell carcinoma (OSCC). However, an infamous limitation arises in situations where SLNs are located in close vicinity of the tracer injection site. In these cases, the hotspot of the injection site can hide adjacent SLNs and hamper the discrimination between tracer injection site and SLNs (shine-through phenomenon). Therefore, technical developments are needed to bring the diagnostic accuracy of SLNB for early-stage OSCC to a higher level. This review evaluates novel SLNB imaging techniques for early-stage OSCC: MR lymphography, CT lymphography, PET lymphoscintigraphy and contrast-enhanced lymphosonography. Furthermore, their reported diagnostic accuracy is described and their relative merits, disadvantages and potential applications are outlined.

Towards automated spectroscopic tissue classification in thyroid and parathyroid surgery.

BACKGROUND: In (para-)thyroid surgery iatrogenic parathyroid injury should be prevented. To aid the surgeons' eye, a camera system enabling parathyroid-specific image enhancement would be useful. Hyperspectral camera technology might work, provided that the spectral signature of parathyroid tissue offers enough specific features to be reliably and automatically distinguished from surrounding tissues. As a first step to investigate this, we examined the feasibility of wide band diffuse reflectance spectroscopy (DRS) for automated spectroscopic tissue classification, using silicon (Si) and indium-gallium-arsenide (InGaAs) sensors. METHODS: DRS (350-1830 nm) was performed during (para-)thyroid resections. From the acquired spectra 36 features at predefined wavelengths were extracted. The best features for classification of parathyroid from adipose or thyroid were assessed by binary logistic regression for Si- and InGaAs-sensor ranges. Classification performance was evaluated by leave-one-out cross-validation. RESULTS: In 19 patients 299 spectra were recorded (62 tissue sites: thyroid = 23, parathyroid = 21, adipose = 18). Classification accuracy of parathyroid-adipose was, respectively, 79% (Si), 82% (InGaAs) and 97% (Si/InGaAs combined). Parathyroid-thyroid classification accuracies were 80% (Si), 75% (InGaAs), 82% (Si/InGaAs combined). CONCLUSIONS: Si and InGaAs sensors are fairly accurate for automated spectroscopic classification of parathyroid, adipose and thyroid tissues. Combination of both sensor technologies improves accuracy. Follow-up research, aimed towards hyperspectral imaging seems justified. Copyright © 2016 John Wiley & Sons, Ltd.

Automated Spectroscopic Tissue Classification in Colorectal Surgery.

BACKGROUND: In colorectal surgery, detecting ureters and mesenteric arteries is of utmost importance to prevent iatrogenic injury and to facilitate intraoperative decision making. A tool enabling ureter- and artery-specific image enhancement within (and possibly through) surrounding adipose tissue would facilitate this need, especially during laparoscopy. To evaluate the potential of hyperspectral imaging in colorectal surgery, we explored spectral tissue signatures using single-spot diffuse reflectance spectroscopy (DRS). As hyperspectral cameras with silicon (Si) and indium gallium arsenide (InGaAs) sensor chips are becoming available, we investigated spectral distinctive features for both sensor ranges. METHODS: In vivo wide-band (wavelength range 350-1830 nm) DRS was performed during open colorectal surgery. From the recorded spectra, 36 features were extracted at predefined wavelengths: 18 gradients and 18 amplitude differences. For classification of respectively ureter and artery in relation to surrounding adipose tissue, the best distinctive feature was selected using binary logistic regression for Si- and InGaAs-sensor spectral ranges separately. Classification performance was evaluated by leave-one-out cross-validation. RESULTS: In 10 consecutive patients, 253 spectra were recorded on 53 tissue sites (including colon, adipose tissue, muscle, artery, vein, ureter). Classification of ureter versus adipose tissue revealed accuracy of 100% for both Si range and InGaAs range. Classification of artery versus surrounding adipose tissue revealed accuracies of 95% (Si) and 89% (InGaAs). CONCLUSIONS: Intraoperative DRS showed that Si and InGaAs sensors are equally suited for automated classification of ureter versus surrounding adipose tissue. Si sensors seem better suited for classifying artery versus mesenteric adipose tissue. Progress toward hyperspectral imaging within this field is promising.

Quantification of heterogeneity as a biomarker in tumor imaging: a systematic review.

BACKGROUND: Many techniques are proposed for the quantification of tumor heterogeneity as an imaging biomarker for differentiation between tumor types, tumor grading, response monitoring and outcome prediction. However, in clinical practice these methods are barely used. This study evaluates the reported performance of the described methods and identifies barriers to their implementation in clinical practice. METHODOLOGY: The Ovid, Embase, and Cochrane Central databases were searched up to 20 September 2013. Heterogeneity analysis methods were classified into four categories, i.e., non-spatial methods (NSM), spatial grey level methods (SGLM), fractal analysis (FA) methods, and filters and transforms (F&T). The performance of the different methods was compared. PRINCIPAL FINDINGS: Of the 7351 potentially relevant publications, 209 were included. Of these studies, 58% reported the use of NSM, 49% SGLM, 10% FA, and 28% F&T. Differentiation between tumor types, tumor grading and/or outcome prediction was the goal in 87% of the studies. Overall, the reported area under the curve (AUC) ranged from 0.5 to 1 (median 0.87). No relation was found between the performance and the quantification methods used, or between the performance and the imaging modality. A negative correlation was found between the tumor-feature ratio and the AUC, which is presumably caused by overfitting in small datasets. Cross-validation was reported in 63% of the classification studies. Retrospective analyses were conducted in 57% of the studies without a clear description. CONCLUSIONS: In a research setting, heterogeneity quantification methods can differentiate between tumor types, grade tumors, and predict outcome and monitor treatment effects. To translate these methods to clinical practice, more prospective studies are required that use external datasets for validation: these datasets should be made available to the community to facilitate the development of new and improved methods.

Differentiation between nerve and adipose tissue using wide-band (350-1,830 nm) in vivo diffuse reflectance spectroscopy.

BACKGROUND: Intraoperative nerve localization is of great importance in surgery. In certain procedures, where nerves show visual resemblance to surrounding adipose tissue, this can be particularly challenging for the human eye. An example of such a delicate procedure is thyroid and parathyroid surgery, where iatrogenic injury of the recurrent laryngeal nerve can result in transient or permanent vocal problems (0.5-2.0% reported incidence). A camera system, enabling nerve-specific image enhancement, would be useful in preventing such complications. This might be realized with hyperspectral camera technology using silicon (Si) or indium gallium arsenide (InGaAs) sensor chips. METHODS: As a first step towards such a camera, we evaluated the performance of diffuse reflectance spectroscopy by analysing spectra collected during 18 thyroid and parathyroid resections. We assessed the contrast information present in two different spectral ranges, for respectively Si and InGaAs sensors. Two hundred fifty three in vivo, wide-band diffuse reflectance spectra (350-1,830 nm range, 1 nm resolution) were acquired on 52 tissue spots, including nerve (n = 22), muscle (n = 12), and adipose tissue (n = 18). We extracted 36 features from these spectroscopic data: 18 gradients and 18 amplitude differences at predefined points in the tissue spectra. Best distinctive feature combinations were established using binary logistic regression. Classification performance was evaluated in a cross-validation (CV) approach by leave-one-out (LOO). To generalize nerve recognition applicability, we performed a train-test (TT) validation using the thyroid and parathyroid surgery data for training purposes and carpal tunnel release surgery data (10 nerve spots and 5 adipose spots) for classification purposes. RESULTS: For combinations of two distinctive spectral features, LOO revealed an accuracy of respectively 78% for Si-sensors and 95% for InGaAs-sensors. TT revealed accuracies of respectively 67% and 100%. CONCLUSIONS: Using diffuse reflectance spectroscopy we have identified that InGaAs sensors are better suited for automated discrimination between nerves and surrounding adipose tissue than Si sensors.

Facilitating tumor functional assessment by spatially relating 3D tumor histology and in vivo MRI: image registration approach.

BACKGROUND: Magnetic resonance imaging (MRI), together with histology, is widely used to diagnose and to monitor treatment in oncology. Spatial correspondence between these modalities provides information about the ability of MRI to characterize cancerous tissue. However, registration is complicated by deformations during pathological processing, and differences in scale and information content. METHODOLOGY/PRINCIPAL FINDINGS: This study proposes a methodology for establishing an accurate 3D relation between histological sections and high resolution in vivo MRI tumor data. The key features of the methodology are: 1) standardized acquisition and processing, 2) use of an intermediate ex vivo MRI, 3) use of a reference cutting plane, 4) dense histological sampling, 5) elastic registration, and 6) use of complete 3D data sets. Five rat pancreatic tumors imaged by T2*-w MRI were used to evaluate the proposed methodology. The registration accuracy was assessed by root mean squared (RMS) distances between manually annotated landmark points in both modalities. After elastic registration the average RMS distance decreased from 1.4 to 0.7 mm. The intermediate ex vivo MRI and the reference cutting plane shared by all three 3D images (in vivo MRI, ex vivo MRI, and 3D histology data) were found to be crucial for the accurate co-registration between the 3D histological data set and in vivo MRI. The MR intensity in necrotic regions, as manually annotated in 3D histology, was significantly different from other histologically confirmed regions (i.e., viable and hemorrhagic). However, the viable and the hemorrhagic regions showed a large overlap in T2(*)-w MRI signal intensity. CONCLUSIONS: The established 3D correspondence between tumor histology and in vivo MRI enables extraction of MRI characteristics for histologically confirmed regions. The proposed methodology allows the creation of a tumor database of spatially registered multi-spectral MR images and multi-stained 3D histology.