Intermittent alternating magnetic fields diminish metal-associated biofilm in vivo.

Prosthetic joint infection (PJI) is a complication of arthroplasty that results in significant morbidity. The presence of biofilm makes treatment difficult, and removal of the prosthesis is frequently required. We have developed a non-invasive approach for biofilm eradication from metal implants using intermittent alternating magnetic fields (iAMF) to generate targeted heating at the implant surface. The goal of this study was to determine whether iAMF demonstrated efficacy in an in vivo implant biofilm infection model. iAMF combined with antibiotics led to enhanced reduction of biofilm on metallic implants in vivo compared to antibiotics or untreated control. iAMF-antibiotic combinations resulted in a > 1 - log further reduction in biofilm burden compared to antibiotics or iAMF alone. This combination effect was seen in both S. aureus and P. aeruginosa and seen with multiple antibiotics used to treat infections with these pathogens. In addition, efficacy was temperature dependent with increasing temperatures resulting in a greater reduction of biofilm. Tissue damage was limited (< 1 mm from implant-tissue interface). This non-invasive approach to eradicating biofilm could serve as a new paradigm in treating PJI.

Improving tremor response to focused ultrasound thalamotomy.

MRI-guided high-intensity focused ultrasound thalamotomy is an incisionless therapy for essential tremor. To reduce adverse effects, the field has migrated to treating at 2 mm above the anterior commissure-posterior commissure plane. We perform MRI-guided high-intensity focused ultrasound with an advanced imaging targeting technique, four-tract tractography. Four-tract tractography uses diffusion tensor imaging to identify the critical white matter targets for tremor control, the decussating and non-decussating dentatorubrothalamic tracts, while the corticospinal tract and medial lemniscus are identified to be avoided. In some patients, four-tract tractography identified a risk of damaging the medial lemniscus or corticospinal tract if treated at 2 mm superior to the anterior commissure-posterior commissure plane. In these patients, we chose to target 1.2-1.5 mm superior to the anterior commissure-posterior commissure plane. In these patients, post-operative imaging revealed that the focused ultrasound lesion extended into the posterior subthalamic area. This study sought to determine if patients with focused ultrasound lesions that extend into the posterior subthalamic area have a differnce in tremor improvement than those without. Twenty essential tremor patients underwent MRI-guided high-intensity focused ultrasound and were retrospectively classified into two groups. Group 1 included patients with an extension of the thalamic-focused ultrasound lesion into the posterior subthalamic area. Group 2 included patients without extension of the thalamic-focused ultrasound lesion into the posterior subthalamic area. For each patient, the percent change in postural tremor, kinetic tremor and Archimedes spiral scores were calculated between baseline and a 3-month follow-up. Two-tailed Wilcoxon rank-sum tests were used to compare the improvement in tremor scores, the total number of sonications, thermal dose to achieve initial tremor response, and skull density ratio between groups. Group 1 had significantly greater postural, kinetic, and Archimedes spiral score percent improvement than Group 2 (P values: 5.41 × 10-5, 4.87 × 10-4, and 5.41 × 10-5, respectively). Group 1 also required significantly fewer total sonications to control the tremor and a significantly lower thermal dose to achieve tremor response (P values: 6.60 × 10-4 and 1.08 × 10-5, respectively). No significant group differences in skull density ratio were observed (P = 1.0). We do not advocate directly targeting the posterior subthalamic area with MRI-guided high-intensity focused ultrasound because the shape of the focused ultrasound lesion can result in a high risk of adverse effects. However, when focused ultrasound lesions naturally extend from the thalamus into the posterior subthalamic area, they provide greater tremor control than those that only involve the thalamus.

Quantifying the relationship between biofilm reduction and thermal tissue damage on metal implants exposed to alternating magnetic fields.

AIM: Metal implant infections are a devastating problem due to the formation of biofilm which impairs the effectiveness of antibiotics and leads to surgical replacement as definitive treatment. Biofilm on metal implants can be reduced using heat generated by alternating magnetic fields (AMF). In this study, the relationship between implant surface biofilm reduction and surrounding tissue thermal damage during AMF exposure is investigated through numerical simulations. METHODS: Mathematical models of biofilm reduction with heat were created based on in vitro experiments. Simulations were performed to predict the spatial and temporal heating on the implant surface and surrounding tissue when exposed to AMF. RESULTS: The modeling results show that intermittent and slow heating can achieve biofilm reduction with a narrow zone of tissue damage around an implant of less than 3 mm. The results also emphasize that uniformity of implant heating is an extremely important factor impacting the effectiveness of biofilm reduction. For a knee implant, using a target temperature of 75 °C, an intermittent treatment strategy of 15 exposures (10 s to target temperature followed by cooldown) achieved a bacterial CFU reduction of 6-log10 across 25% of the implant surface with less than 3 mm of tissue damage. Alternatively, a single 60 s heating exposure to same temperature achieved a bacterial reduction of 6-log10 across 85% of the implant surface, but with 4 mm of tissue damage. CONCLUSION: Overall, this study demonstrates that with uniform heating to temperatures above 70 °C, an implant surface can be largely reduced of biofilm, with only a few mm of surrounding tissue damage.

Feasibility of heating metal implants with alternating magnetic fields (AMF) in scaled up models.

Aim: Treatment of infected orthopedic implants remains a major medical challenge, involving prolonged antibiotic therapy and revision surgery, and adding a >$1 billion annual burden to the health care system in the US alone. Exposure of metallic implants to alternating magnetic fields (AMF) generates heat that can provide a noninvasive means to target biofilm adhered to the surface. In this study, an AMF system with a solenoid coil was constructed for targeting a metal plate surgically implanted in a sheep model.Methods: A tissue-mimicking phantom of the sheep leg was developed along with simulation model of phantom and the live sheep leg. This was used evaluate heating with the AMF system and to compare experimental results with numerical simulations. Comparative AMF exposures were performed/simulated in these model for feasibility of design, verification, and validation of simulations.Results: The system produced magnetic field strengths up to 12mT and achieved plate temperatures of 65-80 °C within 10-14 s. Single and intermittent AMF exposures of a tissue-mimicking phantom agreed with numerical simulations within 5 °C. Similar agreement between experimental measurements and simulations was also observed in the live sheep metal implant model. The simulations also predicted 2-3 mm of tissue damage using a CEM43 thermal dose model for 1-h AMF exposures targeting 65 °C for pulse delays of 2.5 and 5 mins.Conclusion: This study confirmed that AMF technology can be scaled up to treat implants in a large animal model with the same rates of heating and peak temperatures achieved in prior in vitro studies. Further, numerical simulations provided accurate predictions of the heating produced by AMF on metal implants and surrounding tissues, and can be used to design AMF coils for treating human prosthetic joint implants with more complex geometrical shapes.

Focused ultrasound using a novel targeting method four-tract tractography for magnetic resonance-guided high-intensity focused ultrasound targeting.

Magnetic resonance-guided high-intensity focused ultrasound thalamotomy is a Food and Drug Administration-approved treatment for essential tremor. The target, the ventral intermediate nucleus of the thalamus, is not visualized on standard, anatomic MRI sequences. Several recent reports have used diffusion tensor imaging to target the dentato-rubro-thalamic-tract. There is considerable variability in fibre tracking algorithms and what fibres are tracked. Targeting discrete white matter tracts with magnetic resonance-guided high-intensity focused ultrasound is an emerging precision medicine technique that has the promise to improve patient outcomes and reduce treatment times. We provide a technical overview and clinical benefits of our novel, easily implemented advanced tractography method: four-tract tractography. Our method is novel because it targets both the decussating and non-decussating dentato-rubro-thalamic-tracts while avoiding the medial lemniscus and corticospinal tracts. Our method utilizes Food and Drug Administration-approved software and is easily implementable into existing workflows. Initial experience using this approach suggests that it improves patient outcomes by reducing the incidence of adverse effects.

Physical Approaches to Prevent and Treat Bacterial Biofilm.

Prosthetic joint infection (PJI) presents several clinical challenges. This is in large part due to the formation of biofilm which can make infection eradication exceedingly difficult. Following an extensive literature search, this review surveys a variety of non-pharmacological methods of preventing and/or treating biofilm within the body and how they could be utilized in the treatment of PJI. Special attention has been paid to physical strategies such as heat, light, sound, and electromagnetic energy, and their uses in biofilm treatment. Though these methods are still under study, they offer a potential means to reduce the morbidity and financial burden related to multiple stage revisions and prolonged systemic antibiotic courses that make up the current gold standard in PJI treatment. Given that these options are still in the early stages of development and offer their own strengths and weaknesses, this review offers an assessment of each method, the progress made on each, and allows for comparison of methods with discussion of future challenges to their implementation in a clinical setting.

Krabbe Disease: Prospects of Finding a Cure Using AAV Gene Therapy.

Krabbe Disease (KD) is an autosomal metabolic disorder that affects both the central and peripheral nervous systems. It is caused by a functional deficiency of the lysosomal enzyme, galactocerebrosidase (GALC), resulting in an accumulation of the toxic metabolite, psychosine. Psychosine accumulation affects many different cellular pathways, leading to severe demyelination. Although there is currently no effective therapy for Krabbe disease, recent gene therapy-based approaches in animal models have indicated a promising outlook for clinical treatment. This review highlights recent findings in the pathogenesis of Krabbe disease, and evaluates AAV-based gene therapy as a promising strategy for treating this devastating pediatric disease.

A capillary-based microfluidic device enables primary high-throughput room-temperature crystallographic screening.

A novel capillary-based microfluidic strategy to accelerate the process of small-molecule-compound screening by room-temperature X-ray crystallography using protein crystals is reported. The ultra-thin microfluidic devices are composed of a UV-curable polymer, patterned by cleanroom photolithography, and have nine capillary channels per chip. The chip was designed for ease of sample manipulation, sample stability and minimal X-ray background. 3D-printed frames and cassettes conforming to SBS standards are used to house the capillary chips, providing additional mechanical stability and compatibility with automated liquid- and sample-handling robotics. These devices enable an innovative in situ crystal-soaking screening workflow, akin to high-throughput compound screening, such that quantitative electron density maps sufficient to determine weak binding events are efficiently obtained. This work paves the way for adopting a room-temperature microfluidics-based sample delivery method at synchrotron sources to facilitate high-throughput protein-crystallography-based screening of compounds at high concentration with the aim of discovering novel binding events in an automated manner.

Alternating magnetic fields and antibiotics eradicate biofilm on metal in a synergistic fashion.

Hundreds of thousands of human implant procedures require surgical revision each year due to infection. Infections are difficult to treat with conventional antibiotics due to the formation of biofilm on the implant surface. We have developed a noninvasive method to eliminate biofilm on metal implants using heat generated by intermittent alternating magnetic fields (iAMF). Here, we demonstrate that heat and antibiotics are synergistic in biofilm elimination. For Pseudomonas aeruginosa biofilm, bacterial burden was reduced >3 log with iAMF and ciprofloxacin after 24 h compared with either treatment alone (p < 0.0001). This effect was not limited by pathogen or antibiotic as similar biofilm reductions were seen with iAMF and either linezolid or ceftriaxone in Staphylococcus aureus. iAMF and antibiotic efficacy was seen across various iAMF settings, including different iAMF target temperatures, dose durations, and dosing intervals. Initial mechanistic studies revealed membrane disruption as one factor important for AMF enhanced antibacterial activity in the biofilm setting. This study demonstrates the potential of utilizing a noninvasive approach to reduce biofilm off of metallic implants.

AAPM Task Group 241: A medical physicist's guide to MRI-guided focused ultrasound body systems.

Magnetic resonance-guided focused ultrasound (MRgFUS) is a completely non-invasive technology that has been approved by FDA to treat several diseases. This report, prepared by the American Association of Physicist in Medicine (AAPM) Task Group 241, provides background on MRgFUS technology with a focus on clinical body MRgFUS systems. The report addresses the issues of interest to the medical physics community, specific to the body MRgFUS system configuration, and provides recommendations on how to successfully implement and maintain a clinical MRgFUS program. The following sections describe the key features of typical MRgFUS systems and clinical workflow and provide key points and best practices for the medical physicist. Commonly used terms, metrics and physics are defined and sources of uncertainty that affect MRgFUS procedures are described. Finally, safety and quality assurance procedures are explained, the recommended role of the medical physicist in MRgFUS procedures is described, and regulatory requirements for planning clinical trials are detailed. Although this report is limited in scope to clinical body MRgFUS systems that are approved or currently undergoing clinical trials in the United States, much of the material presented is also applicable to systems designed for other applications.

Probing Cerebral Metabolism with Hyperpolarized 13C Imaging after Opening the Blood-Brain Barrier with Focused Ultrasound.

Transient disruption of the blood-brain barrier (BBB) with focused ultrasound (FUS) is an emerging clinical method to facilitate targeted drug delivery to the brain. The focal noninvasive disruption of the BBB can be applied to promote the local delivery of hyperpolarized substrates. In this study, we investigated the effects of FUS on imaging brain metabolism using two hyperpolarized 13C-labeled substrates in rodents: [1-13C]pyruvate and [1-13C]glycerate. The BBB is a rate-limiting factor for pyruvate delivery to the brain, and glycerate minimally passes through the BBB. First, cerebral imaging with hyperpolarized [1-13C]pyruvate resulted in an increase in total 13C signals (p = 0.05) after disrupting the BBB with FUS. Significantly higher levels of both [1-13C]lactate (lactate/total 13C signals, p = 0.01) and [13C]bicarbonate (p = 0.008) were detected in the FUS-applied brain region as compared to the contralateral FUS-unaffected normal-appearing brain region. The application of FUS without opening the BBB in a separate group of rodents resulted in comparable lactate and bicarbonate productions between the FUS-applied and the contralateral brain regions. Second, 13C imaging with hyperpolarized [1-13C]glycerate after opening the BBB showed increased [1-13C]glycerate delivery to the FUS-applied region (p = 0.04) relative to the contralateral side, and [1-13C]lactate production was consistently detected from the FUS-applied region. Our findings suggest that FUS accelerates the delivery of hyperpolarized molecules across the BBB and provides enhanced sensitivity to detect metabolic products in the brain; therefore, hyperpolarized 13C imaging with FUS may provide new opportunities to study cerebral metabolic pathways as well as various neurological pathologies.

Pulsed Focal Ultrasound as a Non-Invasive Method to Deliver Exosomes in the Brain/Stroke.

Exosomes, a component of extracellular vesicles, are shown to carry important small RNAs, mRNAs, protein, and bioactive lipid from parent cells and are found in most biological fluids. Investigators have demonstrated the importance of mesenchymal stem cells derived exosomes in repairing stroke lesions. However, exosomes from endothelial progenitor cells have not been tested in any stroke model, nor has there been an evaluation of whether these exosomes target/home to areas of pathology. Targeted delivery of intravenous administered exosomes has been a great challenge, and a targeted delivery system is lacking to deliver naïve (unmodified) exosomes from endothelial progenitor cells to the site of interest. Pulsed focused ultrasound is being used for therapeutic and experimental purposes. There has not been any report showing the use of low-intensity pulsed focused ultrasound to deliver exosomes to the site of interest in stroke models. In this proof of principle study, we have shown different parameters of pulsed focused ultrasound to deliver exosomes in the intact and stroke brain with or without intravenous administration of nanobubbles. The study results showed that administration of nanobubbles is detrimental to the brain structures (micro bleeding and white matter destruction) at peak negative pressure of >0.25 megapascal, despite enhanced delivery of intravenous administered exosomes. However, without nanobubbles, pulsed focused ultrasound enhances the delivery of exosomes in the stroke area without altering the brain structures.

A CRISPR Screen Reveals Resistance Mechanisms to CD3-Bispecific Antibody Therapy.

CD3-bispecific antibodies represent an important therapeutic strategy in oncology. These molecules work by redirecting cytotoxic T cells to antigen-bearing tumor cells. Although CD3-bispecific antibodies have been developed for several clinical indications, cases of cancer-derived resistance are an emerging limitation to the more generalized application of these molecules. Here, we devised whole-genome CRISPR screens to identify cancer resistance mechanisms to CD3-bispecific antibodies across multiple targets and cancer types. By validating the screen hits, we found that deficiency in IFNγ signaling has a prominent role in cancer resistance. IFNγ functioned by stimulating the expression of T-cell killing-related molecules in a cell type-specific manner. By assessing resistance to the clinical CD3-bispecific antibody flotetuzumab, we identified core fucosylation as a critical pathway to regulate flotetuzumab binding to the CD123 antigen. Disruption of this pathway resulted in significant resistance to flotetuzumab treatment. Proper fucosylation of CD123 was required for its normal biological functions. In order to treat the resistance associated with fucosylation loss, flotetuzumab in combination with an alternative targeting CD3-bispecific antibody demonstrated superior efficacy. Together, our study reveals multiple mechanisms that can be targeted to enhance the clinical potential of current and future T-cell-engaging CD3-bispecific antibody therapies.

3D optical/CT as a preclinical companion imaging platform for glioblastoma drug development.

Multimodality 3D Optical Imaging (OI)/CT has the potential to play a major role in drug development for glioblastomas (GBM), as it is an accessible preclinical method. To demonstrate the potential of 3D OI/CT to visualize orthotopic GBM implantation, we labeled GBM cells with Cy7 and imaged their location using 3D OI/CT. To confirm the accuracy of the spatial localization and demonstrate the ability to image locoregionally delivered therapies, we labeled mouse albumin with Cy7 (Cy7ALB) and delivered it via locoregional infusion 1 mm or 3 mm into the brain and demonstrated correlation of signal between the 3D OI/CT and post necropsy brain slices. In addition, we demonstrated the potential of systemically delivered Cy7ALB contrast to detect blood-brain barrier (BBB) permeability caused by orthotopic GBMs using 3D OI/CT. We also tested the potential of 3D OI/CT to assess focal BBB permeability induced by high intensity focused ultrasound (HIFU), a methodology being used in clinical trials to noninvasively permeabilize the BBB for systemic therapeutic delivery to GBM. We demonstrated the ability of systemic Cy7ALB contrast together with 3D OI/CT to accurately assess real-time HIFU-induced BBB permeability, which correlated to post necropsy imaging of brains. Furthermore, we demonstrated that 3D OI/CT can also image the therapeutic distribution of a Cy7-labeled anti-PD-1 antibody, a prototype translational antibody therapy. We successfully imaged real-time antibody distribution after HIFU-induced BBB permeability, which correlated with post necropsy Cy7 signal and translational PET imaging after injection of [89Zr] anti-PD-1 antibody. Thus, we demonstrated the broad potential of using 3D OI/CT as an accessible preclinical tool to develop anti-GBM therapies.

Consistent opening of the blood brain barrier using focused ultrasound with constant intravenous infusion of microbubble agent.

The blood brain barrier (BBB) is a major obstacle to the delivery of therapeutics to the brain. Focused ultrasound (FUS) in combination with microbubbles can non-invasively open the BBB in a targeted manner. Bolus intravenous injections of microbubbles are standard practice, but dynamic influx and clearance mechanisms prevent delivery of a uniform dose with time. When multiple targets are selected for sonication in a single treatment, uniform serum concentrations of microbubbles are important for consistent BBB opening. Herein, we show that bubble infusions were able to achieve consistent BBB opening at multiple target sites. FUS exposures were conducted with different Definity microbubble concentrations at various acoustic pressures. To quantify the effects of infusion on BBB opening, we calculated the MRI contrast enhancement rate. When infusions were performed at rates of 7.2 µl microbubbles/kg/min or below, we were able to obtain consistent BBB opening without injury at all pressures. However, when infusion rates exceeded 20 µl/kg/min, signs of injury occurred at pressures from 0.39 to 0.56 MPa. When compared to bolus injections, a bubble infusion offers a more controlled and consistent approach to multi-target BBB disruption.

The effect of injected dose on localized tumor accumulation and cardiac uptake of doxorubicin in a Vx2 rabbit tumor model using MR-HIFU mild hyperthermia and thermosensitive liposomes.

PURPOSE: When doxorubicin (DOX) is administered via lyso-thermosensitive liposomes (LTLD), mild hyperthermia enhances localized delivery to heated vs. unheated tumors. The optimal LTLD dose and the impact of different doses on systemic drug distribution are unknown.Materials and methods: In this study, we evaluated local and systemic DOX delivery with three LTLD doses (0.1, 0.5, and 2.5 mg/kg) in a Vx2 rabbit tumor model. Temporally and spatially accurate controlled hyperthermia was achieved using a clinical MR-HIFU system for the intended heating duration (40 min).Results: DOX concentration in tissues delivered from LTLD combined with MR-HIFU mild hyperthermia are dose-dependent, including heated/unheated tumor, heart, and other healthy organs. Higher DOX accumulation and tumor-to-heart drug concentration ratio, defined as the ratio of DOX delivered into the tumor vs the heart, were observed in heated tumors compared to unheated tumors in all three tested doses. The DOX uptake efficiency for each mg/kg of LTLD injected IV of heated tumor was significantly higher than that of unheated tumor and heart within the tested dose range (0.1-2.5 mg/kg). The DOX uptake for the heart linearly scaled up as a function of dose while that for the heated tumor showed some evidence of saturation at the high dose of 2.5 mg/kg.Conclusions: These results provide guidance on clinical protocol design of hyperthermia-triggered drug delivery.

Perfusion-guided sonopermeation of neuroblastoma: a novel strategy for monitoring and predicting liposomal doxorubicin uptake in vivo.

Neuroblastoma (NB) is the most common extracranial solid tumor in infants and children, and imposes significant morbidity and mortality in this population. The aggressive chemoradiotherapy required to treat high-risk NB results in survival of less than 50%, yet is associated with significant long-term adverse effects in survivors. Boosting efficacy and reducing morbidity are therefore key goals of treatment for affected children. We hypothesize that these may be achieved by developing strategies that both focus and limit toxic therapies to the region of the tumor. One such strategy is the use of targeted image-guided drug delivery (IGDD), which is growing in popularity in personalized therapy to simultaneously improve on-target drug deposition and assess drug pharmacodynamics in individual patients. IGDD strategies can utilize a variety of imaging modalities and methods of actively targeting pharmaceutical drugs, however in vivo imaging in combination with focused ultrasound is one of the most promising approaches already being deployed for clinical applications. Over the last two decades, IGDD using focused ultrasound with "microbubble" ultrasound contrast agents (UCAs) has been increasingly explored as a method of targeting a wide variety of diseases, including cancer. This technique, known as sonopermeation, mechanically augments vascular permeability, enabling increased penetration of drugs into target tissue. However, to date, methods of monitoring the vascular bioeffects of sonopermeation in vivo are lacking. UCAs are excellent vascular probes in contrast-enhanced ultrasound (CEUS) imaging, and are thus uniquely suited for monitoring the effects of sonopermeation in tumors. Methods: To monitor the therapeutic efficacy of sonopermeation in vivo, we developed a novel system using 2D and 3D quantitative contrast-enhanced ultrasound imaging (qCEUS). 3D tumor volume and contrast enhancement was used to evaluate changes in blood volume during sonopermeation. 2D qCEUS-derived time-intensity curves (TICs) were used to assess reperfusion rates following sonopermeation therapy. Intratumoral doxorubicin (and liposome) uptake in NB was evalauted ex vivo along with associated vascular changes. Results: In this study, we demonstrate that combining focused ultrasound therapy with UCAs can significantly enhance chemotherapeutic payload to NB in an orthotopic xenograft model, by improving delivery and tumoral uptake of long-circulating liposomal doxorubicin (L-DOX) nanoparticles. qCEUS imaging suggests that changes in flow rates are highly sensitive to sonopermeation and could be used to monitor the efficacy of treatment in vivo. Additionally, initial tumor perfusion may be a good predictor of drug uptake during sonopermeation. Following sonopermeation treatment, vascular biomarkers show increased permeability due to reduced pericyte coverage and rapid onset of doxorubicin-induced apoptosis of NB cells but without damage to blood vessels. Conclusion: Our results suggest that significant L-DOX uptake can occur by increasing tumor vascular permeability with microbubble sonopermeation without otherwise damaging the vasculature, as confirmed by in vivo qCEUS imaging and ex vivo analysis. The use of qCEUS imaging to monitor sonopermeation efficiency and predict drug uptake could potentially provide real-time feedback to clinicians for determining treatment efficacy in tumors, leading to better and more efficient personalized therapies. Finally, we demonstrate how the IGDD strategy outlined in this study could be implemented in human patients using a single case study.

Advanced MRI techniques for transcranial high intensity focused ultrasound targeting.

Magnetic resonance guided high intensity focused ultrasound is a novel, non-invasive, image-guided procedure that is able to ablate intracranial tissue with submillimetre precision. It is currently FDA approved for essential tremor and tremor dominant Parkinson's disease. The aim of this update is to review the limitations of current landmark-based targeting techniques of the ventral intermediate nucleus and demonstrate the role of emerging imaging techniques that are relevant for both magnetic resonance guided high intensity focused ultrasound and deep brain stimulation. A significant limitation of standard MRI sequences is that the ventral intermediate nucleus, dentatorubrothalamic tract, and other deep brain nuclei cannot be clearly identified. This paper provides original, annotated images demarcating the ventral intermediate nucleus, dentatorubrothalamic tract, and other deep brain nuclei on advanced MRI sequences such as fast grey matter acquisition T1 inversion recovery, quantitative susceptibility mapping, susceptibility weighted imaging, and diffusion tensor imaging tractography. Additionally, the paper reviews clinical efficacy of targeting with these novel MRI techniques when compared to current established landmark-based targeting techniques. The paper has widespread applicability to both deep brain stimulation and magnetic resonance guided high intensity focused ultrasound.

Correction: The potent and selective cyclin-dependent kinases 4 and 6 inhibitor ribociclib (LEE011) is a versatile combination partner in preclinical cancer models.

[This corrects the article DOI: 10.18632/oncotarget.26215.].

Quantifying differences in femoral head and neck asphericity in CAM type femoroacetabular impingement and hip dysplasia versus controls using radial 3DCT imaging and volumetric segmentation.

OBJECTIVE: Femoroacetabular impingement (FAI) and hip dysplasia are the most common causes of groin pain originating from the hip joint. To date, there is controversy over cut-off values for the evaluation of abnormal femoral head-neck anatomy with significant overlap between the normal and abnormal hips. Our aim was to perform three-dimensional CT analysis of femoral head and bump anatomy to quantify common hip pathologies (FAI and hip dysplasia) vs controls. METHODS: Consecutive patients who underwent three-dimensional CT imaging for hip dysplasia or CAM type FAI were compared to asymptomatic controls. α angles on radial CT and 3D volumetric femoral head and bump segmentations were performed by two readers. Inter- and intrapatient comparisons were performed including interreader and receiver operating characteristic analyses. RESULTS: 25 FAI patients, 16 hip dysplasia patients and 38 controls were included. FAI and dysplasia patients exhibited higher α angles and higher bump-head volume ratios than the controls (p < 0.05). Larger bump volumes were found among FAI than dysplasia patients and contralateral hips of FAI patients were also different than the controls. α angle at 2 o'clock and bump to head ratio showed the highest area under the curve for patients vs controls. The interreader reliability was better for volumetric segmentation (intraclass correlation coefficient = 0.35-0.84) as compared to the α angles (intraclass correlation coefficient = 0.11-0.44). CONCLUSION: Patients with FAI and dysplasia exhibit different femoral head anatomy than asymptomatic controls. Volumetric segmentation of femoral head and bump is more reliable and better demonstrates the bilateral femoral head anatomy differences in hip patients vs controls. ADVANCES IN KNOWLEDGE: Utilizing information from 3D volumetric bump assessment in patients with FAI and dysplasia, the physicians may be able to more objectively and reliably evaluate the altered anatomy for better pre-surgical evaluation.