Best practices in near-infrared fluorescence imaging with indocyanine green (NIRF/ICG)-guided robotic urologic surgery: a systematic review-based expert consensus.

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.

Anatomical localization of radiocolloid tracer deposition affects outcome of sentinel node procedures in prostate cancer.

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.

The best of both worlds: a hybrid approach for optimal pre- and intraoperative identification of sentinel lymph nodes.

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.

Polyglutamine aggregation in Huntington's disease and spinocerebellar ataxia type 3: similar mechanisms in aggregate formation.

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.

Development and prospects of dedicated tracers for the molecular imaging of bacterial infections.

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.

Clinical trial of combined radio- and fluorescence-guided sentinel lymph node biopsy in breast cancer.

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).

Multimodal surgical guidance towards the sentinel node in vulvar cancer.

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.

Cellular protein quality control and the evolution of aggregates in spinocerebellar ataxia type 3 (SCA3).

AIMS: A characteristic of polyglutamine diseases is the increased propensity of disease proteins to aggregate, which is thought to be a major contributing factor to the underlying neurodegeneration. Healthy cells contain mechanisms for handling protein damage, the protein quality control, which must be impaired or inefficient to permit proteotoxicity under pathological conditions. METHODS: We used a quantitative analysis of immunohistochemistry of the pons of eight patients with the polyglutamine disorder spinocerebellar ataxia type 3. We employed the anti-polyglutamine antibody 1C2, antibodies against p62 that is involved in delivering ubiquitinated protein aggregates to autophagosomes, antibodies against the chaperones HSPA1A and DNAJB1 and the proteasomal stress marker UBB⁺¹. RESULTS: The 1C2 antibody stained neuronal nuclear inclusions (NNIs), diffuse nuclear staining (DNS), granular cytoplasmic staining (GCS) and combinations, with reproducible distribution. P62 always co-localized with 1C2 in NNI. DNS and GCS co-stained with a lower frequency. UBB⁺¹ was present in a subset of neurones with NNI. A subset of UBB⁺¹-containing neurones displayed increased levels of HSPA1A, while DNAJB1 was sequestered into the NNI. CONCLUSION: Based on our results, we propose a model for the aggregation-associated pathology of spinocerebellar ataxia type 3: GCS and DNS aggregation likely represents early stages of pathology, which progresses towards formation of p62-positive NNI. A fraction of NNI exhibits UBB⁺¹ staining, implying proteasomal overload at a later stage. Subsequently, the stress-inducible HSPA1A is elevated while DNAJB1 is recruited into NNIs. This indicates that the stress response is only induced late when all endogenous protein quality control systems have failed.

Sporozoite motility as a quantitative readout for anti-CSP antibody inhibition.

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.

Registration methods for surgical navigation of the mandible: a systematic review.

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.

Interventional nuclear medicine: "click" chemistry as an in vivo targeting strategy for imaging microspheres and bacteria.

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 ∼1 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.

Clustering and Erratic Movement Patterns of Syringe-Injected versus Mosquito-Inoculated Malaria Sporozoites Underlie Decreased Infectivity.

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.

Misframed proteins and neurodegeneration: a novel view on Alzheimer's and Parkinson's diseases.

Sporadic forms of Alzheimer's and Parkinson's diseases are the most frequent forms of their kind. Together with Huntington's disease, they belong to the so called 'conformational diseases' as they share a common feature in the accumulation of insoluble protein deposits. In this review, we focus on the significance of the ubiquitin-proteasome system in conformational diseases and the possible consequences due to the accumulation of aberrant proteins. In all forms of Alzheimer's and Huntington's diseases, but not in Parkinson's disease, we have shown the presence of misframed proteins such as misframed ubiquitin (UBB(+1)) of which we have determined the functional relevance in vitro and in vivo.Misframed proteins are the result of the inaccurate transcription of monotonic sequences in the genome and their subsequent translation. This process has been called 'molecular misreading'. In the present review, we will discuss the present state of the art with regard to UBB(+1) and amyloid precursor protein APP(+1).

Frameshift mutants of beta amyloid precursor protein and ubiquitin-B in Alzheimer's and Down patients.

The cerebral cortex of Alzheimer's and Down syndrome patients is characterized by the presence of protein deposits in neurofibrillary tangles, neuritic plaques, and neuropil threads. These structures were shown to contain forms of beta amyloid precursor protein and ubiquitin-B that are aberrant (+1 proteins) in the carboxyl terminus. The +1 proteins were not found in young control patients, whereas the presence of ubiquitin-B+1 in elderly control patients may indicate early stages of neurodegeneration. The two species of +1 proteins displayed cellular colocalization, suggesting a common origin, operating at the transcriptional level or by posttranscriptional editing of RNA. This type of transcript mutation is likely an important factor in the widely occurring nonfamilial early- and late-onset forms of Alzheimer's disease.

Computational and experimental data on electrostatic density and stacking tendency of asymmetric cyanine 5 dyes.

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).

A prediction model relating the extent of intraoperative fascia preservation to erectile dysfunction after nerve-sparing robot-assisted radical prostatectomy.

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.

Freehand-SPECT with 99mTc-HDP as tool to guide percutaneous biopsy of skeletal lesions detected on bone scintigraphy. / Freehand-SPECT con 99mTc-HDP como herramienta para guiar la biopsia percutánea de lesiones esqueléticas detectadas en la gammagrafía ósea.

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.

Mutant ubiquitin found in Alzheimer's disease causes neuritic beading of mitochondria in association with neuronal degeneration.

A dinucleotide deletion in human ubiquitin (Ub) B messenger RNA leads to formation of polyubiquitin (UbB)+1, which has been implicated in neuronal cell death in Alzheimer's and other neurodegenerative diseases. Previous studies demonstrate that UbB+1 protein causes proteasome dysfunction. However, the molecular mechanism of UbB+1-mediated neuronal degeneration remains unknown. We now report that UbB+1 causes neuritic beading, impairment of mitochondrial movements, mitochondrial stress and neuronal degeneration in primary neurons. Transfection of UbB+1 induced a buildup of mitochondria in neurites and dysregulation of mitochondrial motor proteins, in particular, through detachment of P74, the dynein intermediate chain, from mitochondria and decreased mitochondria-microtubule interactions. Altered distribution of mitochondria was associated with activation of both the mitochondrial stress and p53 cell death pathways. These results support the hypothesis that neuritic clogging of mitochondria by UbB+1 triggers a cascade of events characterized by local activation of mitochondrial stress followed by global cell death. Furthermore, UbB+1 small interfering RNA efficiently blocked expression of UbB+1 protein, attenuated neuritic beading and preserved cellular morphology, suggesting a potential neuroprotective strategy for certain neurodegenerative disorders.

From interventionist imaging to intraoperative guidance: New perspectives by combining advanced tools and navigation with radio-guided surgery. / De la imagen intervencionista a la guía intraoperatoria: nuevas perspectivas combinando herramientas avanzadas y navegación con la cirugía radioguiada.

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.

Dendrimer-encapsulated nanoparticle-core micelles as a modular strategy for particle-in-a-box-in-a-box nanostructures.

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.