ABSTRACT
Antibodies can prevent malaria by neutralizing the infectious Plasmodium falciparum sporozoites (SPZ) before they establish an infection in the liver. Circumsporozoite protein (CSP), the most abundant surface protein of SPZ is the leading candidate for passive (and subunit) immunization approaches against malaria. Comprehensive assessment of the parasite-inhibitory capacity of anti-CSP monoclonal antibodies (mAbs) is an important step in advancing CSP-based immunization strategies. In this study, we employed a quantitative imaging-based motility assay to quantify the effect of anti-CSP mAbs on SPZ motility, both in vitro and in human skin.Our assay provided a quantitative measure of mAb parasite-inhibitory capacity through measurement of the half-maximal motility inhibitory concentration (IC50M) value for anti-CSP mAbs (IC50M 2A10: 24 nM, IC50M 3SP2: 71 nM). We found a sevenfold discrepancy between the IC50M and the binding saturation concentration measured by ELISA, possibly related to the observed shedding of CSP-mAb complexes during SPZ movement. In a subset of SPZ (5%), in vitro motility was unaffected by the presence of 2A10 while 3SP2 was able to completely block movement. In our ex vivo skin explant model, SPZ proved less susceptible to anti-CSP mAbs compared to SPZ in an in vitro environment. By quantitatively assessing motility, we created a valuable tool that can be used for comprehensive assessment of anti-CSP mAb potency. Insight that will help deepen our understanding of anti-CSP mAb potency and guide selection of the most promising anti-CSP mAbs for downstream clinical development.
Subject(s)
Malaria Vaccines , Malaria, Falciparum , Malaria , Animals , Antibodies, Monoclonal/pharmacology , Antibodies, Protozoan , Humans , Malaria/prevention & control , Membrane Proteins , Plasmodium falciparum , Protozoan Proteins , SporozoitesABSTRACT
Image-to-patient registration in navigated mandibular surgery is complex due to the mobile nature of the mandible compared with other craniofacial bones. As a result, surgical navigation is rarely employed in the mandibular region. This systematic review provides an overview of the different registration methods that are used for surgical navigation of the mandible. A systematic search was performed in the MEDLINE Ovid, Scopus, and Embase databases on March 25, 2021. Search terms included synonyms for mandibular surgery, surgical navigation, and registration methods. Articles about navigated mandibular surgery, where the registration method was explicitly mentioned, were included. The database search yielded a total of 2952 articles, from which 81 articles remained for analysis. Four main registration methods were identified: point registration, surface registration, hybrid registration, and computer vision-based registration. The mobility of the mandible is accounted for by either keeping the mandible in a fixed position during preoperative imaging and surgery, or by tracking the mandibular movements. Although different registration methods are available for navigated mandibular surgery, there is always a trade-off between accuracy, registration time, usability, and invasiveness. Future studies should focus on testing the different methods in larger patient studies and should report the registration accuracy.
Subject(s)
Orthognathic Surgical Procedures , Surgery, Computer-Assisted , Humans , Mandible/diagnostic imaging , Mandible/surgery , Surgery, Computer-Assisted/methodsABSTRACT
Malaria vaccine candidates based on live, attenuated sporozoites have led to high levels of protection. However, their efficacy critically depends on the sporozoites' ability to reach and infect the host liver. Administration via mosquito inoculation is by far the most potent method for inducing immunity but highly impractical. Here, we observed that intradermal syringe-injected Plasmodium berghei sporozoites (syrSPZ) were 3-fold less efficient in migrating to and infecting mouse liver than mosquito-inoculated sporozoites (msqSPZ). This was related to a clustered dermal distribution (2-fold-decreased median distance between syrSPZ and msqSPZ) and, more importantly, a 1.4-fold (significantly)-slower and more erratic movement pattern. These erratic movement patterns were likely caused by alteration of dermal tissue morphology (>15-µm intercellular gaps) due to injection of fluid and may critically decrease sporozoite infectivity. These results suggest that novel microvolume-based administration technologies hold promise for replicating the success of mosquito-inoculated live, attenuated sporozoite vaccines.IMPORTANCE Malaria still causes a major burden on global health and the economy. The efficacy of live, attenuated malaria sporozoites as vaccine candidates critically depends on their ability to migrate to and infect the host liver. This work sheds light on the effect of different administration routes on sporozoite migration. We show that the delivery of sporozoites via mosquito inoculation is more efficient than syringe injection; however, this route of administration is highly impractical for vaccine purposes. Using confocal microscopy and automated imaging software, we demonstrate that syringe-injected sporozoites do cluster, move more slowly, and display more erratic movement due to alterations in tissue morphology. These findings indicate that microneedle-based engineering solutions hold promise for replicating the success of mosquito-inoculated live, attenuated sporozoite vaccines.
Subject(s)
Culicidae/parasitology , Injections, Intradermal/methods , Insect Bites and Stings/parasitology , Plasmodium berghei/physiology , Sporozoites/physiology , Syringes , Animals , Drug Delivery Systems , Female , Liver/parasitology , Malaria/prevention & control , Malaria Vaccines/administration & dosage , Mice , Movement , Vaccines, Attenuated/administration & dosageABSTRACT
AIM: Pre-targeting is a proven strategy for in vivo delivery of a diagnostic or therapeutic payload. The pre-targeting concept can be realized through various conjugation strategies, one of which is based on copper-free "click" chemistry. Copper-free click reactions have shown in vivo potential for imaging and radionuclide therapy, but this conjugation strategy has not yet been explored in combination with microspheres or unicellular organisms. This study aims to evaluate the in vivo efficacy of strain-promoted azide-alkyne cycloaddition (SPAAC) reactions to achieve imaging and targeting of azide-functionalized macro-aggregated albumin (MAA) microspheres and Staphylococcus aureus bacteria. METHODS: MAA microspheres (diameter 10-90 µm) were functionalized with a biorthogonal Cy5 fluorophore, bearing an azide functionality (N3), to generate MAA-Cy5-N3. S. aureus (diameter â¼1 µm) were functionalized with 99mTc-UBI29-41-Cy5-N3, generating S. aureus-99mTc-UBI29-41-Cy5-N3. In situ and in vitro click conjugation on the -N3 moieties was studied for 20 h using a radioactivity-based assay and fluorescence microscopy. For in vivo validation, both primary entities, radiolabeled with 99mTc, were deposited into the microvasculature of the liver via intrasplenic injections. Secondary targeting was realized following the intravenous administration of indium-111-radiolabeled diethylenetriaminepentaacetic acid-dibenzocyclooctyne (111In-DTPA-DBCO). To assess click reaction efficiency in vivo, 99mTc and 111In-biodistributions were measured (SPECT and %ID g-1). Use of 111In-DTPA-DBCO in mice without MAA deposits or mice infected with non-functionalized S. aureus served as controls. Ex vivo confocal fluorescence imaging was carried out in excised tissues to confirm the presence of functionalized MAA and bacteria. RESULTS: In vitro data confirmed effective click reactions on both the MAA particles and the bacterial membrane. SPECT imaging and biodistribution studies revealed significantly (p < 0.05) increased accumulation of 111In-DTPA-DBCO at the sites where MAA-Cy5-N3 (7.5 ± 1.5%ID g-1vs. 3.5 ± 0.5%ID g-1 in control mice) and S. aureus-99mTc-UBI29-41-Cy5-N3 (9.3 ± 1.3%ID g-1vs. 6.0 ± 0.5%ID g-1 in control mice) resided. Ex vivo fluorescence imaging confirmed the presence of either functionalized MAA or S. aureus in excised spleens and livers of mice. CONCLUSION: Copper-free click chemistry between a DBCO moiety and Cy5-N3-functionalized microspheres or bacterial entities in the liver can be used to realize in vivo imaging and targeting.
Subject(s)
Click Chemistry , Nuclear Medicine , Animals , Mice , Microspheres , Staphylococcus aureus , Tissue DistributionABSTRACT
PURPOSE: The aim of the present study is to investigate the impact of the near-infrared (NIRF) technology with indocyanine green (ICG) in robotic urologic surgery by performing a systematic literature review and to provide evidence-based expert recommendations on best practices in this field. METHODS: All English language publications on NIRF/ICG-guided robotic urologic procedures were evaluated. We followed the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) statement to evaluate PubMed®, Scopus® and Web of Science™ databases (up to April 2019). Experts in the field provided detailed pictures and intraoperative video-clips of different NIRF/ICG-guided robotic surgeries with recommendations for each procedure. A unique QRcode was generated and linked to each underlying video-clip. This new exclusive feature makes the present the first "dynamic paper" that merges text and figure description with their own video providing readers an innovative, immersive, high-quality and user-friendly experience. RESULTS: Our electronic search identified a total of 576 papers. Of these, 36 studies included in the present systematic review reporting the use of NIRF/ICG in robotic partial nephrectomy (n = 13), robotic radical prostatectomy and lymphadenectomy (n = 7), robotic ureteral re-implantation and reconstruction (n = 5), robotic adrenalectomy (n = 4), robotic radical cystectomy (n = 3), penectomy and robotic inguinal lymphadenectomy (n = 2), robotic simple prostatectomy (n = 1), robotic kidney transplantation (n = 1) and robotic sacrocolpopexy (n = 1). CONCLUSION: NIRF/ICG technology has now emerged as a safe, feasible and useful tool that may facilitate urologic robotic surgery. It has been shown to improve the identification of key anatomical landmarks and pathological structures for oncological and non-oncological procedures. Level of evidence is predominantly low. Larger series with longer follow-up are needed, especially in assessing the quality of the nodal dissection and the feasibility of the identification of sentinel nodes and the impact of these novel technologies on long-term oncological and functional outcomes.
Subject(s)
Coloring Agents , Indocyanine Green , Optical Imaging , Robotic Surgical Procedures/methods , Surgery, Computer-Assisted/methods , Urologic Surgical Procedures/methods , Consensus , Humans , Optical Imaging/standards , Practice Guidelines as Topic , Robotic Surgical Procedures/standards , Surgery, Computer-Assisted/standards , Urologic Surgical Procedures/standardsABSTRACT
PURPOSE: Diagnostic imaging modalities have moderate sensitivity for the identification of lymph node (LN) metastases in prostate cancer (PCa) patients. Mapping the lymphatic drainage from the prostate can help to identify the LNs directly draining from the tumour (sentinel nodes (SNs)); the LNs stated to have the highest chance of containing metastatic cancer cells. Although the lymphatic drainage may differ between segments within the prostate, the location of the primary tumour is not routinely taken into account during peripheral zone-aimed tracer administration. This study evaluates whether linking the SN procedure to the primary cancer deposits increases the identification accuracy of lymphatic metastases. METHODS: Sixty-seven PCa patients, scheduled for robot-assisted laparoscopic prostatectomy (RALP) and extended lymph node dissection (ePLND) with subsequent SN biopsy, were included in this retrospective study. After injection of the hybrid tracer ICG-99mTc-nanocolloid in the prostate, SN mapping was performed based on lymphoscintigraphy and SPECT/CT. SNs were resected using a combination of radio- and fluorescence guidance. Pathology was used to determine the primary tumour location and metastatic spread. Fluorescence imaging of paraffin-embedded prostate tissue was used to determine the location of the tracer deposits in the prostate. This deposition was related to the primary tumour location, the lymphatic drainage pattern of the injected tracer, and the metastatic spread. RESULTS: In total 265 radioactive LNs (211 SNs and 54 higher-echelon nodes in 64 patients; 4.3 LNs per patient; IQR: 2-6) were identified. In three patients (4%) preoperative imaging did not allow identification of SNs. Tumour-positive SN visualization within the pelvis was shown to be influenced by intraprostatic location of tracer administration. This could be concluded from (1) a clear correlation between lymphatic drainage to the right or left side of the body and tracer deposition on the right or left side of the prostate, (2) visualization of a higher number of LNs after dorsal tracer deposition compared with ventral tracer deposition, (3) different drainage patterns observed for tracer deposition into the base or apex of the prostate, and (4) the indication that intratumoural tracer deposition increases the chance of visualizing nodal metastases compared with extratumoural tracer deposition. CONCLUSIONS: The correlation between the location of the tracer deposits, the location of the primary tumour, and the visualization of the (tumour-positive) SNs indicated that placement of tracer deposits is of influence on the visualized lymphatic drainage pattern. This suggests that tracer injection near or into the primary tumour site is beneficial for the identification of metastatic spread.
Subject(s)
Prostatic Neoplasms/pathology , Sentinel Lymph Node/surgery , Colloids , Humans , Intraoperative Period , Male , Neoplasm Metastasis , Preoperative Period , Prostatic Neoplasms/surgery , Radioactive Tracers , Retrospective Studies , Sentinel Lymph Node/pathologyABSTRACT
PURPOSE: To assess the feasibility of using freehand Single Photon Emission Computed Tomography (freehandSPECT) for the identification of technetium-99m-hydroxydiphosphonate (99mTc-HDP) positive bone lesions and to evaluate the possibility of using these imaging data-sets for augmented- and virtual-reality based navigation approaches. MATERIAL AND METHODS: In 20 consecutive patients referred for scintigraphy with 99mTc-HDP, 21 three-dimensional freehandSPECT-images were generated using a handheld gamma camera. Concordance of the two different data sets was ranked. Furthermore, feasibility of segmenting the hotspot of tracer accumulation for navigation purposes was assessed. RESULTS: In 86% of the cases freehandSPECT images showed good concordance with the corresponding part of the scintigraphic images. In lesions with a signal to background ratio (SBR) >1.36, freehandSPECT provided an automatically segmented reference point for navigation purposes. In 14% of the cases (average SBR 1.82, range 1.0-3.4) freehandSPECT images showed intermediate concordance due to difficult anatomical area or negative bone scintigraphy and could not be used as navigation targets. CONCLUSION: In this pilot study, in 86% of the cases freehandSPECT demonstrated good concordance with traditional scintigraphy. A lesion with a SBR of 1.36 or more was suitable for navigation. These high-quality freehandSPECT images supported the future exploration navigation strategies, e.g. guided needle biopsies.
Subject(s)
Biopsy, Needle/methods , Bone Diseases/diagnostic imaging , Gamma Cameras , Image-Guided Biopsy/methods , Technetium Tc 99m Medronate/analogs & derivatives , Tomography, Emission-Computed, Single-Photon/methods , Bone Diseases/pathology , Bone Neoplasms/diagnostic imaging , Bone Neoplasms/secondary , Double-Blind Method , Equipment Design , Humans , Image-Guided Biopsy/instrumentation , Organ Specificity , Phantoms, Imaging , Pilot Projects , Radiopharmaceuticals/pharmacokinetics , Software , Technetium Tc 99m Medronate/pharmacokinetics , Tomography, Emission-Computed, Single-Photon/instrumentation , Whole Body ImagingABSTRACT
Far-red dyes such as cyanine 5 (Cy5) are gaining interest in (bio)medical diagnostics as they have promising features in terms of stability and brightness. Here, the electrostatic density and stacking tendency in different solvents of nine systematically altered asymmetrical Cy5 dyes are reported. In addition to this, the influence of molecular alterations on the vibronic coupling was reported. The data presented supplement to the recent study "The influence of systematic structure alterations on the photophysical properties and conjugation characteristics of asymmetric cyanine 5 dyes" (Spa et al., 2018).
ABSTRACT
Robot-assisted radical prostatectomy (RARP) is performed in patients with prostate cancer. Unfortunately, 10-46% of patients may still suffer from limited erectile function (EF) after RARP. This study aimed to develop a prediction model based on the extent of fascia preservation (FP) and postoperative EF after RARP. A previously developed FP score quantizing the extent and regions of nerve-preservation was determined in a cohort of 1241 patients who underwent RARP. The predictive value of the FP score for post-prostatectomy EF (following the international index erectile function (IIEF) score, EF domain) was analyzed. To increase the predictive value of the scoring system, the FP regions were related to postoperative EF, nerve distribution and co-morbidity factors. Finally, a prediction model for EF was developed based on the studied cohort. When corrected for the preoperative IIEF-EF, the FP score was shown to be a significant denominator for IIEF (p = 2.5 × 10- 15) with an R2 of 35%. Variable selection performed using the Akaike information criterion led to a final prediction model for postoperative IIEF after nerve-preservation based on the FP score. Furthermore, patient's age, preoperative IIEF score, CCIS and use of clips for nerve sparing were significantly associated with postoperative IIEF-EF. More anterior fascia preservation was correlated with better EF outcome and age was a strong independent predictor of EF outcome. In older men, the relative benefit of more extensive fascia preservation was at least similar to younger men, despite a lower baseline IIEF-EF score. Quantitative nerve-sparing FP scoring could be related to the postoperative IIEF-EF and integrated into a multivariate prediction model, which includes with age, use of surgical clips, the Charlson Comorbidity Index Score (CCIS), and preoperative IIEF-EF. When further validated the prediction model could provide patients and care-givers a qualitative estimation of EF outcome after RARP.
Subject(s)
Erectile Dysfunction/epidemiology , Erectile Dysfunction/etiology , Fascia , Models, Statistical , Organ Sparing Treatments , Postoperative Complications/etiology , Prostatectomy/methods , Prostatic Neoplasms/surgery , Robotic Surgical Procedures/methods , Aged , Cohort Studies , Erectile Dysfunction/physiopathology , Humans , Male , Middle Aged , Penile Erection/physiology , Predictive Value of Tests , Prostatectomy/adverse effects , Recovery of Function/physiology , Robotic Surgical Procedures/adverse effects , Treatment OutcomeABSTRACT
PURPOSE: Hybrid image-guided surgery technologies such as combined radio- and fluorescence-guidance are increasingly gaining interest, but their added value still needs to be proven. In order to evaluate if and how fluorescence-guidance can help realize improvements beyond the current state-of-the-art in sentinel node (SN) biopsy procedures, use of the hybrid tracer indocyanine green (ICG)-99mTc-nancolloid was evaluated in a large cohort of patients. PATIENTS AND METHODS: A prospective trial was conducted (n = 501 procedures) in a heterogeneous cohort of 495 patients with different malignancies (skin malignancies, oral cavity cancer, penile cancer, prostate cancer and vulva cancer). After injection of ICG-99mTc-nanocolloid, SNs were preoperatively identified based on lymphoscintigraphy and SPECT/CT. Intraoperatively, SNs were pursued via gamma tracing, visual identification (blue dye) and/or near-infrared fluorescence imaging during either open surgical procedures (head and neck, penile, vulvar cancer and melanoma) or robot assisted laparoscopic surgery (prostate cancer). As the patients acted as their own control, use of hybrid guidance could be compared to conventional radioguidance and the use of blue dye (n = 300). This was based on reported surgical complications, overall survival, LN recurrence free survival, and false negative rates (FNR). RESULTS: A total of 1,327 SN-related hotspots were identified on 501 preoperative SPECT/CT scans. Intraoperatively, a total number of 1,643 SNs were identified based on the combination of gamma-tracing (>98%) and fluorescence-guidance (>95%). In patients wherein blue dye was used (n = 300) fluorescence-based SN detection was superior over visual blue dye-based detection (22-78%). No adverse effects related to the use of the hybrid tracer or the fluorescence-guidance procedure were found and outcome values were not negatively influenced. CONCLUSION: With ICG-99mTc-nanocolloid, the SN biopsy procedure has become more accurate and independent of the use of blue dye. With that, the procedure has evolved to be universal for different malignancies and anatomical locations.
Subject(s)
Preoperative Period , Sentinel Lymph Node Biopsy/methods , Humans , Intraoperative PeriodABSTRACT
The integration of medical imaging technologies into diagnostic and therapeutic approaches can provide a preoperative insight into both anatomical (e.g. using computed tomography, magnetic resonance imaging, or ultrasound), as well as functional aspects (e.g. using single photon emission computed tomography, positron emission tomography, lymphoscintigraphy, or optical imaging). Moreover, some imaging modalities are also used in an interventional setting (e.g. computed tomography, ultrasound, gamma or optical imaging) where they provide the surgeon with real-time information during the procedure. Various tools and approaches for image-guided navigation in cancer surgery are becoming feasible today. With the development of new tracers and portable imaging devices, these advances will reinforce the role of interventional molecular imaging.
Subject(s)
Inventions , Neoplasms/diagnostic imaging , Radiography, Interventional/methods , Surgery, Computer-Assisted/methods , Computer Systems , Female , Fluorescent Dyes/analysis , Humans , Laparoscopy , Luminescent Measurements , Male , Multimodal Imaging , Neoplasm Metastasis , Neoplasms/surgery , Preoperative Care , Radiography, Interventional/trends , Radiopharmaceuticals , Robotic Surgical Procedures , Sentinel Lymph Node Biopsy , Single Photon Emission Computed Tomography Computed Tomography , Surgery, Computer-Assisted/trendsABSTRACT
The hierarchically controlled synthesis and characterization of self-assembling macromolecules and particles are key to explore and exploit new nanomaterials. Here we present a versatile strategy for constructing particle-in-a-box-in-a-box systems by assembling dendrimer-encapsulated gold nanoparticles (DENs) into dendrimicelles. This is realized by combining positively charged PAMAM dendrimers with a negative-neutral block copolymer. The number of particles per dendrimicelle can be controlled by mixing DENs with empty PAMAM dendrimers. The dendrimicelles are stable in solution for months and provide improved resistance for the nanoparticles against degradation. The dendrimicelle strategy provides a flexible platform with a plethora of options for variation in the type of nanoparticles, dendrimers and block copolymers used, and hence is tunable for applications ranging from nanomedicine to catalysis.
ABSTRACT
BACKGROUND: Nodal metastases are linked to poor outcome in men with penile or prostate cancer. Early detection and resection are important for staging and for the prognosis. However, lymphadenectomy is associated with morbidity and may miss metastases when performed solely on the basis of anatomical templates. METHODS: In this article we describe the technique and benefits of sentinel node biopsy (SNB) and provide a review of the literature. RESULTS: Dynamic sentinel node techniques using both radioactive and optical (hybrid) tracers have been proven effective in penile cancer. For prostate cancer, SNB added to extended nodal dissection may further tailor dissection to the highly variable lymphatic drainage patterns in the pelvis. The sensitivity of SNB was found to be superior to conventional imaging methods; however, false-negative SNB procedures can occur and a complementary extensive lymphadenectomy is required to remove additional positive nodes that were not detected in the SNB template. CONCLUSION: SNB is a standard method for early detection of nodal metastases in penile cancer and provides superior diagnostic accuracy to conventional imaging modalities in prostate cancer.
Subject(s)
Penile Neoplasms/pathology , Prostatic Neoplasms/pathology , Sentinel Lymph Node Biopsy/methods , Sentinel Lymph Node/diagnostic imaging , Sentinel Lymph Node/pathology , Single Photon Emission Computed Tomography Computed Tomography/methods , Early Detection of Cancer/methods , Humans , Image-Guided Biopsy/methods , Lymphatic Metastasis , Male , Penile Neoplasms/diagnostic imaging , Prostatic Neoplasms/diagnosis , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
PURPOSE: To assess if combined fluorescence- and radio-guided occult lesion localization (hybrid ROLL) is feasible in patients scheduled for surgical resection of non-palpable (18)F-FDG-avid lesions on PET/CT. METHODS: Four patients with (18)F-FDG-avid lesions on follow-up PET/CT that were not palpable during physical examination but were suspected to harbor metastasis were enrolled. Guided by ultrasound, the hybrid tracer indocyanine green (ICG)-(99m)Tc-nanocolloid was injected centrally in the target lesion. SPECT/CT imaging was used to confirm tracer deposition. Intraoperatively, lesions were localized using a hand-held gamma ray detection probe, a portable gamma camera, and a fluorescence camera. After excision, the gamma camera was used to check the wound bed for residual activity. RESULTS: A total of six (18)F-FDG-avid lymph nodes were identified and scheduled for hybrid ROLL. Comparison of the PET/CT images with the acquired SPECT/CT after hybrid tracer injection confirmed accurate tracer deposition. No side effects were observed. Combined radio- and fluorescence-guidance enabled localization and excision of the target lesion in all patients. Five of the six excised lesions proved tumor-positive at histopathology. CONCLUSION: The hybrid ROLL approach appears to be feasible and can facilitate the intraoperative localization and excision of non-palpable lesions suspected to harbor tumor metastases. In addition to the initial radioguided detection, the fluorescence component of the hybrid tracer enables high-resolution intraoperative visualization of the target lesion. The procedure needs further evaluation in a larger cohort and wider range of malignancies to substantiate these preliminary findings.
Subject(s)
Fluorodeoxyglucose F18 , Hodgkin Disease/diagnostic imaging , Indocyanine Green , Melanoma/diagnostic imaging , Positron Emission Tomography Computed Tomography , Radiopharmaceuticals , Technetium Tc 99m Aggregated Albumin , Adult , Aged , Female , Hodgkin Disease/pathology , Humans , Melanoma/secondary , Multimodal ImagingABSTRACT
AIMS: Polyglutamine (polyQ) diseases are characterized by the expansion of a polymorphic glutamine sequence in disease-specific proteins and exhibit aggregation of these proteins. This is combated by the cellular protein quality control (PQC) system, consisting of chaperone-mediated refolding as well as proteasomal and lysosomal degradation pathways. Our recent study in the polyQ disease spinocerebellar ataxia type 3 (SCA3) suggested a distinct pattern of protein aggregation and PQC dysregulation. METHODS: To corroborate these findings we have investigated immunohistochemically stained 5 µm sections from different brain areas of Huntington's disease (HD) and SCA3 patients. RESULTS: Irrespective of disease and brain region, we observed peri- and intranuclear polyQ protein aggregates. A subset of neurones with intranuclear inclusions bodies exhibited signs of proteasomal dysfunction, up-regulation of HSPA1A and re-distribution of DNAJB1. The extent of the observed effects varied depending on brain area and disease protein. CONCLUSIONS: Our results suggest a common sequence, in which formation of cytoplasmic and nuclear inclusions precede proteasomal impairment and induction of the cellular stress response. Clearly, impairment of the PQC is not the primary cause for inclusion formation, but rather a consequence that might contribute to neuronal dysfunction and death. Notably, the inclusion pathology is not directly correlated to the severity of the degeneration in different areas, implying that different populations of neurones respond to polyQ aggregation with varying efficacy and that protein aggregation outside the neuronal perikaryon (e.g. axonal aggregates) or other effects of polyQ aggregation, which are more difficult to visualize, may contribute to neurodegeneration.
Subject(s)
Brain/pathology , Huntington Disease/pathology , Machado-Joseph Disease/pathology , Peptides/metabolism , Protein Aggregation, Pathological/pathology , Adult , Aged , Aged, 80 and over , Brain/metabolism , Female , Humans , Huntington Disease/metabolism , Immunohistochemistry , Intranuclear Inclusion Bodies/metabolism , Intranuclear Inclusion Bodies/pathology , Machado-Joseph Disease/metabolism , Male , Middle Aged , Nerve Degeneration/metabolism , Nerve Degeneration/pathology , Neurons/pathology , Protein Aggregation, Pathological/metabolismABSTRACT
The popularity gained by the sentinel lymph node (SLN) procedure in the last two decades did increase the interest of the surgical disciplines for other applications of radioguided surgery. An example is the gamma-probe guided localization of occult or difficult to locate neoplastic lesions. Such guidance can be achieved by intralesional delivery (ultrasound, stereotaxis or CT) of a radiolabelled agent that remains accumulated at the site of the injection. Another possibility rested on the use of systemic administration of a tumour-seeking radiopharmaceutical with favourable tumour accumulation and retention. On the other hand, new intraoperative imaging devices for radioguided surgery in complex anatomical areas became available. All this a few years ago led to the delineation of the concept Guided intraOperative Scintigraphic Tumour Targeting (GOSTT) to include the whole spectrum of basic and advanced nuclear medicine procedures required for providing a roadmap that would optimise surgery. The introduction of allied signatures using, e.g. hybrid tracers for simultaneous detection of the radioactive and fluorescent signals did amply the GOSTT concept. It was now possible to combine perioperative nuclear medicine imaging with the superior resolution of additional optical guidance in the operating room. This hybrid approach is currently in progress and probably will become an important model to follow in the coming years. A cornerstone in the GOSTT concept is constituted by diagnostic imaging technologies like SPECT/CT. SPECT/CT was introduced halfway the past decade and was immediately incorporated into the SLN procedure. Important reasons attributing to the success of SPECT/CT were its combination with lymphoscintigraphy, and the ability to display SLNs in an anatomical environment. This latter aspect has significantly been improved in the new generation of SPECT/CT cameras and provides the base for the novel mixed reality protocols of image-guided surgery. In these protocols the generated virtual SPECT/CT elements are visually superimposed in the body of the patient in the operating room to directly facilitate, by means of visualization on screen or using head-mounted devices, the localization of radioactive and/or fluorescent targets by minimal invasive approaches in areas of complex anatomy. All these technological advances will play an increasing role in the future extension and the clinical impact of the GOSTT concept.
Subject(s)
Image-Guided Biopsy/methods , Neoplasms/diagnosis , Neoplasms/surgery , Sentinel Lymph Node Biopsy/methods , Surgery, Computer-Assisted/methods , Tomography, Emission-Computed, Single-Photon/methods , User-Computer Interface , Evidence-Based Medicine , Female , Humans , Lymph Nodes/pathology , Lymph Nodes/surgery , Lymphatic Metastasis , Male , Multimodal Imaging/methods , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
PURPOSE: Recent innovations such as preoperative SPECT/CT, intraoperative imaging using portable devices and a hybrid tracer were evaluated in a multimodality approach for sentinel node (SN) mapping and biopsy in head and neck malignancies. MATERIAL AND METHODS: The evaluation included 25 consecutive patients with head and neck malignancies (16 melanomas and 9 oral cavity squamous cell carcinomas). Patients were peritumorally injected with the hybrid tracer ICG-(99m)Tc-nanocolloid. SNs were initially identified with lymphoscintigraphy followed by single photon emission computed tomography (SPECT/CT) 2 hours after tracer administration. During surgery a portable gamma camera in combination with a near-infrared fluorescence camera was used in addition to a handheld gamma ray detection probe to locate the SNs. RESULTS: In all patients the use of conventional lymphoscintigraphy, SPECT/CT and the additional help of the portable gamma camera in one case were able to depict a total of 67 SNs (55 of them visualized on planar images, 11 additional on SPECT/CT and 1 additional with the portable gamma camera). A total of 67 of the preoperatively defined SNs together with 22 additional SNs were removed intraoperatively; 12 out of the 22 additional SNs found during operation were located in the vicinity of the injection site in anatomical areas such as the periauricular or submental regions. The other 10 additional SNs were found by radioguided post-resection control of the excision SN site. CONCLUSION: In the present series 26% additional SNs were found using the multimodal approach, that incorporates SPECT/CT and intraoperative imaging to the conventional procedure. This approach appears to be useful in malignancies located close to the area of lymphatic drainage such as the periauricular area and the oral cavity.
Subject(s)
Gamma Cameras , Head and Neck Neoplasms/diagnostic imaging , Head and Neck Neoplasms/pathology , Lymphoscintigraphy , Multimodal Imaging , Sentinel Lymph Node Biopsy/methods , Tomography, Emission-Computed, Single-Photon , Adult , Aged , Female , Humans , Male , Middle AgedABSTRACT
Bacterial infections have always been, and still are, a major global healthcare problem. For accurate treatment it is of upmost importance that the location(s), severity, type of bacteria, and therapeutic response can be accurately staged. Similar to the recent successes in oncology, tracers specific for molecular imaging of the disease may help advance patient management. Chemical design and bacterial targeting mechanisms are the basis for the specificity of such tracers. The aim of this review is to provide a comprehensive overview of the molecular imaging tracers developed for optical and nuclear identification of bacteria and bacterial infections. Hereby we envision that such tracers can be used to diagnose infections and aid their clinical management. From these compounds we have set out to identify promising targeting mechanisms and select the most promising candidates for further development.
Subject(s)
Bacterial Infections/diagnosis , Molecular Imaging/methods , Radioactive Tracers , Animals , Bacteria/cytology , Bacteria/drug effects , Bacteria/metabolism , Bacteria/virology , Bacterial Infections/drug therapy , Humans , Isotope LabelingABSTRACT
INTRODUCTION: Conventional sentinel node (SN) mapping is performed by injecting a radiocolloid followed by lymphoscintigraphy (and SPECT/CT imaging). An extra intraoperative injection with blue dye can then allow for optical identification of the SN. In order to improve the current clinical standard, the hybrid tracer indocyanine green (ICG)-(99m)Tc-nanocolloid was introduced, a tracer that is both radioactive and fluorescent. This feasibility study aimed to evaluate the value of a multimodal-based SN biopsy in vulvar cancer. MATERIALS AND METHODS: Fifteen patients with vulvar cancer (29 groins) scheduled for SN biopsy were peritumorally injected with ICG-(99m)Tc-nanocolloid followed by lymphoscintigraphy and SPECT/CT imaging to identify the SNs. In thirteen patients, shortly before the start of the operation, blue dye was intradermally injected around the lesion. SNs were harvested using a combination of radiotracing, fluorescence imaging, and optical blue dye detection. A portable gamma camera was used before and after SN excision to confirm excision of the preoperatively defined SNs. RESULTS: Preoperative lymphoscintigraphy and SPECT/CT imaging visualized drainage to 39 SNs in 28 groins. During the operation, 98% (ex vivo 100%) of the SNs were radioactive. With fluorescence imaging 96% of the SNs (ex vivo 100%) could be visualized. Only 65% of the SNs had stained blue at the time of excision. CONCLUSION: ICG-(99m)Tc-nanocolloid can be used for preoperative SN identification and enables multimodal (radioactive and fluorescent) surgical guidance in patients with vulvar cancer. The addition of fluorescence-based optical guidance offers more effective SN visualization compared to blue dye.
Subject(s)
Lymph Nodes/pathology , Lymph Nodes/surgery , Vulvar Neoplasms/pathology , Vulvar Neoplasms/surgery , Adult , Aged , Aged, 80 and over , Female , Humans , Indocyanine Green , Lymph Nodes/diagnostic imaging , Middle Aged , Multimodal Imaging , Neoplasm Staging , Radiopharmaceuticals , Sentinel Lymph Node Biopsy/methods , Technetium Tc 99m Aggregated Albumin , Tomography, Emission-Computed, Single-Photon , Tomography, X-Ray Computed , Vulvar Neoplasms/diagnostic imaging , Young AdultABSTRACT
BACKGROUND: Combining radioactive colloids and a near-infrared (NIR) fluorophore permits preoperative planning and intraoperative localization of deeply located sentinel lymph nodes (SLNs) with direct optical guidance by a single lymphatic tracer. The aim of this clinical trial was to evaluate and optimize a hybrid NIR fluorescence and radioactive tracer for SLN detection in patients with breast cancer. METHODS: Patients with breast cancer undergoing SLN biopsy were enrolled. The day before surgery, a periareolar injection of indocyanine green (ICG)-99mTc-radiolabelled nanocolloid was administered and a lymphoscintigram acquired. Blue dye was injected immediately before surgery. Intraoperative SLN localization was performed using a γ probe and the Mini-FLARE™ NIR fluorescence imaging system. Patients were divided into two dose groups, with one group receiving twice the particle density of ICG and nanocolloid, but the same dose of radioactive 99mTc. RESULTS: Thirty-two patients were enrolled in the trial. At least one SLN was identified before and during operation. All 48 axillary SLNs could be detected by γ tracing and NIR fluorescence imaging, but only 42 of them stained blue. NIR fluorescence imaging permitted detection of lymphatic vessels draining to the SLN up to 29 h after injection. Doubling the particle density did not yield a difference in fluorescence intensity (median 255 (range 98-542) versus 284 (90-921) arbitrary units; P = 0.590) or signal-to-background ratio (median 5·4 (range 3·0-15·4) versus 4·9 (3·5-16·3); P = 1·000) of the SLN. CONCLUSION: The hybrid NIR fluorescence and radioactive tracer permitted accurate preoperative and intraoperative detection of the SLNs in patients with breast cancer. REGISTRATION NUMBER: NTR3685 (Netherlands Trial Register; http://www.trialregister.nl).